sGC STIMULATORS

ABSTRACT

Compounds of Formulae I′ and I are described, which are useful as stimulators of sGC, particularly NO-independent, heme-dependent stimulators. These compounds are also useful for treating, preventing or managing various disorders that are herein disclosed.

This application is a continuation of U.S. patent application Ser. No.16/817,830, filed Mar. 13, 2020, which is a continuation of U.S. patentapplication Ser. No. 16/178,771, filed Nov. 2, 2018, now U.S. Pat. No.10,639,308, which is a continuation of U.S. patent application Ser. No.15/245,697, filed Aug. 24, 2016, now U.S. Pat. No. 10,183,021; which isa divisional of U.S. patent application Ser. No. 14/774,954, filed Sep.14, 2015, now U.S. Pat. No. 9,481,689; which is a national stage entryof International Patent Application No. PCT/US2014/028370, filed Mar.14, 2014; which claims the benefit of priority from U.S. ProvisionalApplication Nos. 61/914,915, filed Dec. 11, 2013 and 61/790,637, filedMar. 15, 2013. Each of the aforementioned applications is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

The present disclosure relates to stimulators of soluble guanylatecyclase (sGC), pharmaceutical formulations comprising them and theiruses thereof, alone or in combination with one or more additionalagents, for treating and/or preventing various diseases, wherein anincrease in the concentration of nitric oxide (NO) or an increase in theconcentration of cyclic Guanosine Monophosphate (cGMP) might bedesirable.

BACKGROUND OF THE INVENTION

Soluble guanylate cyclase (sGC) is the primary receptor for nitric oxide(NO) in vivo. sGC can be activated via both NO-dependent andNO-independent mechanisms. In response to this activation, sGC convertsGTP into the secondary messenger cyclic GMP (cGMP). The increased levelof cGMP, in turn, modulates the activity of downstream effectorsincluding protein kinases, phosphodiesterases (PDEs) and ion channels.

In the body, NO is synthesized from arginine and oxygen by variousnitric oxide synthase (NOS) enzymes and by sequential reduction ofinorganic nitrate. Three distinct isoforms of NOS have been identified:inducible NOS (iNOS or NOS II) found in activated macrophage cells;constitutive neuronal NOS (nNOS or NOS I), involved in neurotransmissionand long term potentiation; and constitutive endothelial NOS (eNOS orNOS III) which regulates smooth muscle relaxation and blood pressure.

Experimental and clinical evidence indicates that reducedbioavailability and/or responsiveness to endogenously produced NOcontributes to the development of cardiovascular, endothelial, renal andhepatic disease, as well as erectile dysfunction and other sexualdisorders (e.g. female sexual disorder or vaginal atrophy). Inparticular, the NO signaling pathway is altered in cardiovasculardiseases, including, for instance, systemic and pulmonary hypertension,heart failure, angina, stroke, thrombosis and other thromboembolicdiseases, peripheral arterial disease, fibrosis of the liver, lung orkidney and atherosclerosis.

sGC stimulators are also useful in the treatment of lipid relateddisorders such as e.g., dyslipidemia, hypercholesterolemia,hypertriglyceridemia, sitosterolemia, fatty liver disease, andhepatitis.

Pulmonary hypertension (PH) is a disease characterized by sustainedelevation of blood pressure in the pulmonary vasculature (pulmonaryartery, pulmonary vein and pulmonary capillaries), which results inright heart hypertrophy, eventually leading to right heart failure anddeath. In PH, the bioactivity of NO and other vasodilators such asprostacyclin is reduced, whereas the production of endogenousvasoconstrictors such as endothelin is increased, resulting in excessivepulmonary vasoconstriction. sGC stimulators have been used to treat PHbecause they promote smooth muscle relaxation, which leads tovasodilation.

Treatment with NO-independent sGC stimulators also promoted smoothmuscle relaxation in the corpus cavernosum of healthy rabbits, rats andhumans, causing penile erection, indicating that sGC stimulators areuseful for treating erectile dysfunction.

NO-independent, heme-dependent, sGC stimulators, such as those disclosedherein, have several important differentiating characteristics,including crucial dependency on the presence of the reduced prostheticheme moiety for their activity, strong synergistic enzyme activationwhen combined with NO and stimulation of the synthesis of cGMP by directstimulation of sGC, independent of NO. The benzylindazole compound YC-1was the first sGC stimulator to be identified. Additional sGCstimulators with improved potency and specificity for sGC have sincebeen developed. These compounds have been shown to produceanti-aggregatory, anti-proliferative and vasodilatory effects.

Since compounds that stimulate sGC in an NO-independent manner offerconsiderable advantages over other current alternative therapies, thereis a need to develop novel stimulators of sGC. They are potentiallyuseful in the prevention, management and treatment of disorders such aspulmonary hypertension, arterial hypertension, heart failure,atherosclerosis, inflammation, thrombosis, renal fibrosis and failure,liver cirrhosis, lung fibrosis, erectile dysfunction, female sexualarousal disorder and vaginal atrophy and other cardiovascular disorders;they are also potentially useful for the prevention, management andtreatment of lipid related disorders.

SUMMARY OF THE INVENTION

The present invention is directed to compounds according to Formula I′,or pharmaceutically acceptable salts thereof,

wherein X¹ is selected from N, CH, C(C₁₋₄alkyl), C(C₁₋₄haloalkyl), CCland CF;X² is independently selected from N or C;W is eitheri) absent, with J^(B) connected directly to the carbon atom bearing twoJ groups, each J is independently selected from hydrogen or methyl, n is1 and J^(B) is a C₁₋₇ alkyl chain optionally substituted by up to 9instances of fluorine; wherein, optionally, one —CH₂— unit of said C₁₋₇alkyl chain can be replaced by —O— or —S—.ii) a ring B that is a phenyl or a 5 or 6-membered heteroaryl ring,containing 1 or 2 ring heteroatoms selected from N, O or S; wherein withring B being the phenyl or 5 or 6-membered heteroaryl ring; each J ishydrogen; n is an integer selected from 0 to 3; and each J^(B) isindependently selected from halogen, —CN, a C₁₋₆ aliphatic, —OR^(B) or aC₃₋₈ cycloaliphatic group; wherein each said C₁₋₆ aliphatic and eachsaid C₃₋₈ cycloaliphatic group is optionally and independentlysubstituted with up to 3 instances of R³; each R^(B) is independentlyselected from hydrogen, a C₁₋₆ aliphatic or a C₃₋₈ cycloaliphatic;wherein each of said R^(B) that is a C₁₋₆ aliphatic and each of saidR^(B) that is a C₃₋₈ cycloaliphatic ring is optionally and independentlysubstituted with up to 3 instances of R^(3a);each R³ is independently selected from halogen, —CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄haloalkyl);each R^(3a) is independently selected from halogen, —CN, C₁₋₄ alkyl,C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄haloalkyl);o is an integer selected from 1 to 3;each J^(D) is independently selected from J^(A), halogen, —CN, —NO₂,—OR^(D), —SR^(D), —C(O)R^(D), —C(O)OR^(D), —OC(O)R^(D), —C(O)N(R^(D))₂,—N(R^(D))₂, —N(R^(d))C(O)R^(D), —N(R^(d))C(O)OR^(D),N(R^(d))C(O)N(R^(D))₂, —OC(O)N(R^(D))₂, —SO₂R^(D), —SO₂N(R^(D))₂,—N(R^(d))SO₂R^(D), a C₁₋₆ aliphatic, —(C₁₋₆ aliphatic)-R^(D), a C₃₋₈cycloaliphatic ring, a 6 to 10-membered aryl ring, a 4 to 8-memberedheterocyclic ring or a 5 to 10-membered heteroaryl ring; wherein eachsaid 4 to 8-membered heterocyclic ring and each said 5 to 10-memberedheteroaryl ring contains between 1 and 3 heteroatoms independentlyselected from O, N or S; and wherein each said C₁₋₆ aliphatic, each saidC₁₋₆ aliphatic portion of the —(C₁₋₆ aliphatic)-R^(D) moiety, each saidC₃₋₈ cycloaliphatic ring, each said 6 to 10-membered aryl ring, eachsaid 4 to 8-membered heterocyclic ring and each said 5 to 10-memberedheteroaryl ring is optionally and independently substituted with up to 5instances of R^(5d), wherein at least one J^(D) is not hydrogen;J^(A) is selected from hydrogen, halogen, methyl, hydroxyl, methoxy,trifluoromethyl, trifluoromethoxy or —NR^(a)R^(b); wherein R^(a) andR^(b) are each independently selected from hydrogen, C₁₋₆ alkyl or a 3-6cycloalkyl ring; or wherein R^(a) and R^(b), together with the nitrogenatom to which they are both attached, form a 4-8 membered heterocyclicring, or a 5-membered heteroaryl ring optionally containing up to twoadditional heteroatoms selected from N, O and S; wherein each of said4-8 membered heterocyclic ring and 5-membered heteroaryl ring isoptionally and independently substituted by up to 6 instances offluorine;each R^(D) is independently selected from hydrogen, a C₁₋₆ aliphatic,—(C₁₋₆ aliphatic)-R^(f), a C₃₋₈ cycloaliphatic ring, a 4 to 10-memberedheterocyclic ring, phenyl or a 5 to 6-membered heteroaryl ring; whereineach said 4 to 10-membered heterocyclic ring and each said 5 to6-membered heteroaryl ring contains between 1 and 3 heteroatomsindependently selected from O, N or S; and wherein each said C₁₋₆aliphatic, each said C₁₋₆ aliphatic portion of the —(C₁₋₆aliphatic)-R^(f) moiety, each said C₃₋₈ cycloaliphatic ring, each said 4to 10-membered heterocyclic ring, each said phenyl and each said 5 to6-membered heteroaryl ring is optionally and independently substitutedwith up to 5 instances of R^(5a); wherein when any R^(D) is one of aC₁₋₆ aliphatic or a —(C₁₋₆ aliphatic)-R^(f) group, one or two —CH₂—units that form said C₁₋₆ aliphatic chains may, optionally, be replacedby a group independently selected from —N(R^(d))—, —CO— or —O—; providedthat when X¹ is one of CH, C(C₁₋₄ alkyl), C(C₁₋₄haloalkyl), CCl or CF;X² is C; and at least one J^(D) is —N(R^(D))₂ and is attached to one ofthe pyrimidine ring D carbons ortho to the two nitrogen atoms of saidring D, one instance of R^(D) is not a pyridine or a pyrimidine;each R^(d) is independently selected from hydrogen, a C₁₋₆ aliphatic,—(C₁₋₆ aliphatic)-R^(f), a C₃₋₈ cycloaliphatic ring, a 4 to 8-memberedheterocyclic ring, phenyl or a 5 to 6-membered heteroaryl ring; whereineach said 4 to 8-membered heterocyclic ring and each said 5 or6-membered heteroaryl ring contains between 1 and 3 heteroatomsindependently selected from O, N or S; and wherein each said C₁₋₆aliphatic, each said C₁₋₆ aliphatic portion of the —(C₁₋₆aliphatic)-R^(f) moiety, each said C₃₋₈ cycloaliphatic ring, each said 4to 8-membered heterocyclic ring, each said phenyl and each said 5 to6-membered heteroaryl ring is optionally and independently substitutedby up to 5 instances of R^(5b); wherein when any R^(d) is one of a C₁₋₆aliphatic or a —(C₁₋₆ aliphatic)-R^(f) group, one or two —CH₂— unitsthat form said C₁₋₆ aliphatic chains may, optionally, be replaced by agroup independently selected from —N(R^(d))—, —CO— or —O—;each R^(f) is independently selected from a C₁₋₃ alkyl, a C₃₋₈cycloaliphatic ring, a 4 to 10-membered heterocyclic ring, phenyl or a 5to 6-membered heteroaryl ring; wherein each said 4 to 10-memberedheterocyclic ring and each said 5 to 6-membered heteroaryl ring containsbetween 1 and 4 heteroatoms independently selected from O, N or S; andwherein each said C₃₋₈ cycloaliphatic ring, each said 4 to 10-memberedheterocyclic ring, each said phenyl and each said 5 to 6-memberedheteroaryl ring is optionally and independently substituted by up to 5instances of R^(5c);when J^(D) is —C(O)N(R^(D))₂, —N(R^(D))₂, —N(R^(d))C(O)N(R^(D))₂,—OC(O)N(R^(D))₂ or —SO₂N(R^(D))₂, the two R^(D) groups together with thenitrogen atom attached to the two R^(D) groups may form a 4 to8-membered heterocyclic ring or a 5-membered heteroaryl ring; whereineach said 4 to 8-membered heterocyclic ring and each said 5-memberedheteroaryl ring optionally contains up to 3 additional heteroatomsindependently selected from N, O or S, in addition to the nitrogen atomto which the two R^(D) groups are attached; and wherein each said 4 to8-membered heterocyclic ring and each said 5-membered heteroaryl ring isoptionally and independently substituted by up to 5 instances of R⁵;when J^(D) is —N(R^(d))C(O)R^(D), the R^(D) group together with thecarbon atom attached to the R^(D) group, with the nitrogen atom attachedto the R^(d) group, and with the R^(d) group may form a 4 to 8-memberedheterocyclic ring or a 5-membered heteroaryl ring; wherein each said 4to 8-membered heterocyclic ring and each said 5-membered heteroaryl ringoptionally contains up to 2 additional heteroatoms independentlyselected from N, O or S, in addition to the nitrogen atom to which theR^(d) group is attached; and wherein each said 4 to 8-memberedheterocyclic ring and each said 5-membered heteroaryl ring is optionallyand independently substituted by up to 5 instances of R⁵;when J^(D) is —N(R^(d))C(O)OR^(D), the R^(D) group together with theoxygen atom attached to the R^(D) group, with the carbon atom of the—C(O)— portion of the —N(R^(d))C(O)OR^(D) group, with the nitrogen atomattached to the R^(d) group, and with said R^(d) group, may form a 4 to8-membered heterocyclic ring; wherein said 4 to 8-membered heterocyclicring optionally contains up to 2 additional heteroatoms independentlyselected from N, O or S, and is optionally and independently substitutedby up to 5 instances of R⁵;when J^(D) is —N(R^(d))C(O)N(R^(D))₂, one of the R^(D) groups attachedto the nitrogen atom, together with said nitrogen atom, and with the Natom attached to the R^(d) group and said R^(d) group may form a 4 to8-membered heterocyclic ring; wherein said 4 to 8-membered heterocyclicring optionally contains up to 2 additional heteroatoms independentlyselected from N, O or S, and is optionally and independently substitutedby up to 5 instances of R⁵;when J^(D) is —N(R^(d))SO₂R^(D), the R^(D) group together with thesulfur atom attached to the R^(D) group, with the nitrogen atom attachedto the R^(d) group, and with said R^(d) group may combine to form a 4 to8-membered heterocyclic ring; wherein said 4 to 8-membered heterocyclicring optionally contains up to 2 additional heteroatoms independentlyselected from N, O or S, and is optionally and independently substitutedby up to 5 instances of R⁵;each R⁵ is independently selected from halogen, —CN, C₁₋₆ alkyl, —(C₁₋₆alkyl)-R⁶, —OR⁶, —SR⁶, —COR⁶, —OC(O)R⁶, —C(O)OR⁶, —C(O)N(R⁶)₂,—C(O)N(R⁶)SO₂R⁶, —N(R⁶)C(O)R⁶, —N(R⁶)C(O)OR⁶, —N(R⁶)C(O)N(R⁶)₂, —N(R⁶)₂,—SO₂R⁶, —SO₂OH, —SO₂NHOH, —SO₂N(R⁶)₂, —SO₂N(R⁶)COOR⁶, —SO₂N(R⁶)C(O)R⁶,—N(R⁶)SO₂R⁶, —(C═O)NHOR⁶, a C₃₋₈ cycloalkyl ring, a 4 to 7-memberedheterocyclic ring, a 5 or 6-membered heteroaryl ring, phenyl, benzyl, anoxo group or a bicyclic group; wherein each of said 5 or 6-memberedheteroaryl ring or 4 to 7-membered heterocyclic ring contains up to 4ring heteroatoms independently selected from N, O and S; and whereineach of said C₁₋₆ alkyl, C₁₋₆ alkyl portion of the —(C₁₋₆ alkyl)-R⁶moiety, C₃₋₈ cycloalkyl ring, 4 to 7-membered heterocyclic ring, 5 or6-membered heteroaryl ring, benzyl or phenyl group is optionally andindependently substituted with up to 3 instances of halogen, C₁₋₄ alkyl,—OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —CONH₂,—COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo; whereinsaid bicyclic group contains ring one and ring two in a fused or bridgedrelationship, said ring one is a 4 to 7-membered heterocyclic ring, a 5or 6-membered heteroaryl ring, phenyl or benzyl, and said ring two is aphenyl ring or a 5 or 6-membered heteroaryl ring containing up to 3 ringheteroatoms selected from N, O or S; and wherein said bicyclic group isoptionally and independently substituted by up to six instances ofhalogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN,—COOH, —CONH₂, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) oroxo;two instances of R⁵, attached to the same or different atoms of J^(D),together with said atom or atoms to which they are attached, mayoptionally form a C₃₋₈ cycloalkyl ring, a 4 to 6-membered heterocyclicring; a phenyl or a 5 or 6-membered heteroaryl ring, resulting in abicyclic system wherein the two rings of the bicyclic system are in aspiro, fused or bridged relationship, wherein said 4 to 6-memberedheterocycle or said 5 or 6-membered heteroaryl ring contains up to fourring heteroatoms independently selected from N, O or S; and wherein saidC₃₋₈ cycloalkyl ring, 4 to 6-membered heterocyclic ring, phenyl or 5 or6-membered heteroaryl ring is optionally and independently substitutedby up to 3 instances of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, oxo, —C(O)O(C₁₋₄ alkyl), —C(O)OH, —NR(CO)O(C₁₋₄ alkyl),—CONH₂, —OH or halogen; wherein R is hydrogen or a C₁₋₂ alkyl;each R^(5a) and each R^(5b) is independently selected from halogen, —CN,C₁₋₆ alkyl, —(C₁₋₆ alkyl)R^(6a), —OR^(6a), —SR^(6a), —COR^(6a),—OC(O)R^(6a), —C(O)OR^(6a), —C(O)N(R^(6a))₂, —C(O)N(R^(6a))SO₂R^(6a),—N(R^(6a))C(O)R^(6a),—N(R^(6a))C(O)OR^(6a), —N(R^(6a))C(O)N(R^(6a))₂,—N(R^(6a))₂, —SO₂R^(6a), —SO₂OH, —SO₂NHOH, —SO₂N(R^(6a))₂,—SO₂N(R^(6a))COOR^(6a), —SO₂N(R^(6a))C(O)R^(6a), —N(R^(6a))SO₂R^(6a),—(C═O)NHOR^(6a), a C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclicring, a 5 or 6-membered heteroaryl ring, phenyl, benzyl, an oxo group ora bicyclic group; wherein each 5 or 6-membered heteroaryl ring or 4 to7-membered heterocyclic ring contains up to 4 ring heteroatomsindependently selected from N, O and S, wherein each of said C₁₋₆ alkyl,C₁₋₆ alkyl portion of the —(C₁₋₆ alkyl)R^(6a) moiety, C₃₋₈ cycloalkylring, 4 to 7-membered heterocyclic ring, 5 or 6-membered heteroarylring, benzyl or phenyl group is optionally and independently substitutedwith up to 3 instances of halogen, C₁₋₄ alkyl, C₁₋₄haloalkyl, —OH, —NH₂,—NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —CONH₂, —COO(C₁₋₄ alkyl),—O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo; wherein said bicyclic groupcontains ring one and ring two in a fused or bridged relationship, saidring one is a 4 to 7-membered heterocyclic ring, a 5 or 6-memberedheteroaryl ring, phenyl or benzyl, and said ring two is a phenyl ring ora 5 or 6-membered heteroaryl ring containing up to 3 ring heteroatomsselected from N, O or S; and wherein said bicyclic group is optionallyand independently substituted by up to six instances of halogen, C₁₋₄alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —CONH₂,—COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo;two instances of R^(5a) or two instances of R^(5b) attached to the sameor different atoms of R^(D) or R^(d), respectively, together with saidatom or atoms to which they are attached, may optionally form a C₃₋₈cycloalkyl ring, a 4 to 6-membered heterocyclic ring; a phenyl or a 5 or6-membered heteroaryl ring, resulting in a bicyclic system wherein thetwo rings of the bicyclic system are in a spiro, fused or bridgedrelationship with respect to each other; wherein said 4 to 6-memberedheterocycle or said 5 or 6-membered heteroaryl ring contains up to fourring heteroatoms independently selected from N, O or S; and wherein saidC₃₋₈ cycloalkyl ring, 4 to 6-membered heterocyclic ring, phenyl or 5 or6-membered heteroaryl ring is optionally and independently substitutedby up to 3 instances of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy,C₁₋₄haloalkoxy, oxo, —C(O)O(C₁₋₄ alkyl), —C(O)OH, —C(O)NH₂,—NR(CO)O(C₁₋₄ alkyl), —OH or halogen; wherein R is hydrogen or a C₁₋₂alkyl;each R^(5c) is independently selected from halogen, —CN, C₁₋₆ alkyl,—(C₁₋₆ alkyl)-R^(6b), —OR^(6b), —SR^(6b), —COR^(6b), —OC(O)R^(6b),—C(O)OR^(6b), —C(O)N(R^(6b))₂, —C(O)N(R^(6b))SO₂R^(6b),—N(R^(6b))C(O)R^(6b), —N(R^(6b))C(O)OR^(6b), —N(R^(6b))C(O)N(R^(6b))₂,—N(R^(6b))₂, —SO₂R^(6b), —SO₂OH, —SO₂NHOH, —SO₂N(R^(6b))₂,—SO₂N(R^(6b))COOR^(6b), —SO₂N(R^(6b))C(O)R^(6b), —N(R^(6b))SO₂R^(6b),—(C═O)NHOR^(6b), a C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclicring, a 5 or 6-membered heteroaryl ring, phenyl, benzyl, an oxo group,or a bicyclic group; wherein each of said 5 or 6-membered heteroarylring and each of said 4 to 7-membered heterocyclic ring contains up to 4ring heteroatoms independently selected from N, O and S; and whereineach of said C₁₋₆ alkyl, C₁₋₆ alkyl portion of said —(C₁₋₆ alkyl)-R^(6b)moiety, each of said C₃₋₈ cycloalkyl ring, each of said 4 to 7-memberedheterocyclic ring, each of said 5 or 6-membered heteroaryl ring, each ofsaid benzyl and each of said phenyl group is optionally andindependently substituted with up to 3 instances of halogen, C₁₋₄ alkyl,—OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —CONH₂,—COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo; whereinsaid bicyclic group contains a first ring and a second ring in a fusedor bridged relationship, said first ring is a 4 to 7-memberedheterocyclic ring, a 5 or 6-membered heteroaryl ring, phenyl or benzyl,and said second ring is a phenyl ring or a 5 or 6-membered heteroarylring containing up to 3 ring heteroatoms selected from N, O or S; andwherein said bicyclic group is optionally and independently substitutedby up to six instances of halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —CONH₂, —COO(C₁₋₄ alkyl), —O(C₁₋₄alkyl), —O(C₁₋₄ haloalkyl) or oxo;two instances of R^(5c) attached to the same or different atoms ofR^(f), together with said atom or atoms to which it is attached, mayoptionally form a C₃₋₈ cycloalkyl ring, a 4 to 6-membered heterocyclicring; a phenyl or a 5 or 6-membered heteroaryl ring, resulting in abicyclic system wherein the two rings of the bicyclic system are in aspiro, fused or bridged relationship with respect to each other; whereinsaid 4 to 6-membered heterocycle or said 5 or 6-membered heteroaryl ringcontains up to four ring heteroatoms independently selected from N, O orS; and wherein said C₃₋₈ cycloalkyl ring, 4 to 6-membered heterocyclicring, phenyl or 5 or 6-membered heteroaryl ring is optionally andindependently substituted by up to 3 instances of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, oxo, —C(O)O(C₁₋₄ alkyl),—C(O)OH, —CONH₂, —NR(CO)O(C₁₋₄ alkyl), —OH or halogen; wherein R ishydrogen or a C₁₋₂ alkyl;each R^(5d) is independently selected from halogen, —CN, C₁₋₆ alkyl,—(C₁₋₆ alkyl)-R⁶, —OR⁶, —SR⁶, —COR⁶, —OC(O)R⁶, —C(O)OR⁶, —C(O)N(R⁶)₂,—N(R⁶)C(O)R⁶, —N(R⁶)C(O)OR⁶, —N(R⁶)C(O)N(R⁶)₂, —N(R⁶)₂, —SO₂R⁶, —SO₂OH,—SO₂NHOH, —SO₂N(R⁶)COR⁶, —SO₂N(R⁶)₂, —N(R⁶)SO₂R⁶, a C₇₋₁₂ aralkyl, aC₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclic ring, a 5 or6-membered heteroaryl ring, phenyl or an oxo group; wherein each 5 or6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring containsup to four ring heteroatoms independently selected from N, O and S,wherein each of said C₁₋₆ alkyl, C₁₋₆ alkyl portion of the —(C₁₋₆alkyl)-R⁶ moiety, C₇₋₁₂ aralkyl, C₃₋₈ cycloalkyl ring, 4 to 7-memberedheterocyclic ring, 5 or 6-membered heteroaryl ring or phenyl group isoptionally and independently substituted with up to 3 instances ofhalogen, C₁₋₄ alkyl, C₁₋₄ (haloalkyl), —OH, —NH₂, —NH(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)₂, —CN, —COOH, —CONH₂, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl),—O(C₁₋₄ haloalkyl) or oxo;two instances of R^(5d) attached to the same or different atoms ofJ^(D), together with said atom or atoms of J^(D) to which they areattached, may optionally form a C₃₋₈ cycloalkyl ring, a 4 to 6-memberedheterocyclic ring; a phenyl or a 5 or 6-membered heteroaryl ring,resulting in a bicyclic system wherein the two rings of the bicyclicsystem are in a spiro, fused or bridged relationship with respect toeach other; wherein said 4 to 6-membered heterocycle or said 5 or6-membered heteroaryl ring contains up to four ring heteroatomsindependently selected from N, O or S; and wherein said C₃₋₈ cycloalkylring, 4 to 6-membered heterocyclic ring, phenyl or 5 or 6-memberedheteroaryl ring is optionally and independently substituted by up to 3instances of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,oxo, —C(O)O(C₁₋₄ alkyl), —C(O)OH, —NR(CO)O(C₁₋₄ alkyl), —C(O)NH₂, —OH orhalogen; wherein R is hydrogen or a C₁₋₂ alkyl;each R⁶ is independently selected from hydrogen, a C₁₋₆ alkyl, phenyl,benzyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclic ring or a5 or 6-membered heteroaryl ring, wherein each of said C₁₋₆ alkyl, eachof said phenyl, each of said benzyl, each of said C₃₋₈ cycloalkyl group,each of said 4 to 7-membered heterocyclic ring and each of said 5 or6-membered heteroaryl ring is optionally and independently substitutedwith up to 3 instances of halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —C(O)NH₂, —COO(C₁₋₄ alkyl), —O(C₁₋₄alkyl), —O(C₁₋₄ haloalkyl) or oxo, wherein each of said 5 or 6-memberedheteroaryl ring or 4 to 7-membered heterocyclic ring contains up to 4ring heteroatoms independently selected from N, O and S;each R^(6a) is independently selected from hydrogen, a C₁₋₆ alkyl,phenyl, benzyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclicring or a 5 or 6-membered heteroaryl ring, wherein each of said C₁₋₆alkyl, each of said phenyl, each of said benzyl, each of said C₃₋₈cycloalkyl group, each of said 4 to 7-membered heterocyclic ring andeach of said 5 or 6-membered heteroaryl ring is optionally andindependently substituted with up to 3 instances of halogen, C₁₋₄ alkyl,—OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —C(O)NH₂,—C(O)N(C₁₋₆ alkyl)₂, —C(O)NH(C₁₋₆ alkyl), —C(O)N(C₁₋₆ haloalkyl)₂,—C(O)NH(C₁₋₆ haloalkyl), C(O)N(C₁₋₆ alkyl)(C₁₋₆ haloalkyl), —COO(C₁₋₆alkyl), —COO(C₁₋₆ haloalkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo,wherein each of said 5 or 6-membered heteroaryl ring or 4 to 7-memberedheterocyclic ring contains up to 4 ring heteroatoms independentlyselected from N, O and S;each R^(6b) is independently selected from hydrogen, a C₁₋₆ alkyl,phenyl, benzyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclicring or a 5 or 6-membered heteroaryl ring, wherein each of said C₁₋₆alkyl, each of said phenyl, each of said benzyl, each of said C₃₋₈cycloalkyl group, each of said 4 to 7-membered heterocyclic ring andeach of said 5 or 6-membered heteroaryl ring is optionally andindependently substituted with up to 3 instances of halogen, C₁₋₄ alkyl,—OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —C(O)NH₂,—COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo, whereineach of said 5 or 6-membered heteroaryl ring or 4 to 7-memberedheterocyclic ring contains up to 4 ring heteroatoms independentlyselected from N, O and S; whereintwo instances of R⁶ linked to the same nitrogen atom of R⁵ or R^(5d),together with said nitrogen atom of R⁵ or R^(5d), respectively, may forma 5 to 8-membered heterocyclic ring or a 5-membered heteroaryl ring;wherein each said 5 to 8-membered heterocyclic ring and each said5-membered heteroaryl ring optionally contains up to 2 additionalheteroatoms independently selected from N, O or S;two instances of R^(6a) linked to a nitrogen atom of R^(5a) or R^(5b),together with said nitrogen, may form a 5 to 8-membered heterocyclicring or a 5-membered heteroaryl ring; wherein each said 5 to 8-memberedheterocyclic ring and each said 5-membered heteroaryl ring optionallycontains up to 2 additional heteroatoms independently selected from N, Oor S;two instances of R^(6b) linked to a nitrogen atom of R^(5c), togetherwith said nitrogen, may form a 5 to 8-membered heterocyclic ring or a5-membered heteroaryl ring; wherein each said 5 to 8-memberedheterocyclic ring and each said 5-membered heteroaryl ring optionallycontains up to 2 additional heteroatoms independently selected from N, Oor S;two J^(D) groups attached to two vicinal ring D atoms, taken togetherwith said two vicinal ring D atoms, may form a 5 to 7-memberedheterocycle or a 5-membered heteroaryl ring that is fused to ring D;wherein said 5 to 7-membered heterocycle or said 5-membered ringheteroaryl contains from 1 to 3 heteroatoms independently selected fromN, O or S; and wherein said 5 to 7-membered heterocycle or said5-membered heteroaryl ring is optionally and independently substitutedby up to 3 instances of oxo or —(Y)—R⁹;wherein Y is either absent or is a linkage in the form of a C₁₋₆ alkylchain, optionally substituted by up to 6 instances of fluoro; andwherein when Y is said C₁₋₆ alkyl chain, up to 3 methylene units of thisalkyl chain, can be replaced by a group selected from —O—, —C(O)— or—N((Y)—R⁹⁰)—, wherein

-   -   i) when Y is absent, each R⁹⁰ is independently selected from        hydrogen, —COR¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂, —C(O)N(R¹⁰)SO₂R¹⁰,        —SO₂R¹⁰, —SO₂N(R¹⁰)₂, —SO₂N(R¹⁰)COOR¹⁰, —SO₂N(R¹⁰)C(O)R¹⁰,        —(C═O)NHOR¹⁰, C₃₋₆ cycloalkyl ring, a 4-8-membered heterocyclic        ring, a phenyl ring or a 5-6 membered heteroaroaryl ring;        wherein each said 4 to 8-membered heterocyclic ring or 5 to        6-membered heteroaryl ring contains up to 4 ring heteroatoms        independently selected from N, O or S; and wherein each of said        C₃₋₆ cycloalkyl rings, each of said 4 to 8-membered heterocyclic        rings, each of said phenyl and each of said 5 to 6-membered        heteroaryl rings is optionally and independently substituted        with up to 3 instances of R¹¹; and    -   ii) when Y is present, each R⁹⁰ is independently selected from        hydrogen, halogen, —CN, —OR¹⁰, —COR¹⁰, —OC(O)R¹⁰, —C(O)OR¹⁰,        —C(O)N(R¹⁰)₂, —C(O)N(R¹⁰)SO₂R¹⁰, —N(R¹⁰)C(O)R¹⁰,        —N(R¹⁰)C(O)OR¹⁰, —N(R¹⁰)C(O)N(R¹⁰)₂, —N(R¹⁰)₂, —SO₂R¹⁰,        —SO₂N(R¹⁰)₂, —SO₂N(R¹⁰)COOR¹⁰, —SO₂N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)SO₂R¹⁰,        —(C═O)NHOR¹⁰, C₃₋₆ cycloalkyl ring, a 4-8-membered heterocyclic        ring, a phenyl ring or a 5-6 membered heteroaroaryl ring;        wherein each said 4 to 8-membered heterocyclic ring or 5 to        6-membered heteroaryl ring contains up to 4 ring heteroatoms        independently selected from N, O or S; and wherein each of said        C₃₋₆ cycloalkyl rings, each of said 4 to 8-membered heterocyclic        rings, each of said phenyl and each of said 5 to 6-membered        heteroaryl rings is optionally and independently substituted        with up to 3 instances of R¹¹;        each R⁹ is independently selected from hydrogen, halogen, —CN,        —OR¹⁰, —COR¹⁰, —OC(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂,        —C(O)N(R¹⁰)SO₂R¹⁰, —N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)C(O)OR¹⁰,        —N(R¹⁰)C(O)N(R¹⁰)₂, —N(R¹⁰)₂, —SO₂R¹⁰, —SO₂N(R¹⁰)₂,        —SO₂N(R¹⁰)COOR¹⁰, —SO₂N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)SO₂R¹⁰,        —(C═O)NHOR¹⁰, C₃₋₆ cycloalkyl ring, a 4-8-membered heterocyclic        ring, a phenyl ring or a 5-6 membered heteroaryl ring; wherein        each said 4 to 8-membered heterocyclic ring or 5 to 6-membered        heteroaryl ring contains up to 4 ring heteroatoms independently        selected from N, O or S; and wherein each of said C₃₋₆        cycloalkyl rings, each of said 4 to 8-membered heterocyclic        rings, each of said phenyl and each of said 5 to 6-membered        heteroaryl rings is optionally and independently substituted        with up to 3 instances of R¹¹;        each R¹⁰ is independently selected from hydrogen, a C₁₋₆ alkyl,        —(C₁₋₆ alkyl)-R¹³, phenyl, benzyl, a C₃₋₈ cycloalkyl ring, a 4        to 7-membered heterocyclic ring or a 5 or 6-membered heteroaryl        ring, wherein each 5 or 6-membered heteroaryl ring or 4 to        7-membered heterocyclic ring contains up to 4 ring heteroatoms        independently selected from N, O and S; and wherein each of said        C₁₋₆ alkyl, C₁₋₆ alkyl portion of said —(C₁₋₆ alkyl)-R¹³ moiety,        each said phenyl, each said benzyl, each said C₃₋₈ cycloalkyl        group, each said 4 to 7-membered heterocyclic ring and each 5 or        6-membered heteroaryl ring is optionally and independently        substituted with up to 3 instances of R^(11a);        each R¹³ is independently selected from a phenyl, a benzyl, a        C₃₋₆ cycloalkyl ring, a 4 to 7-membered heterocyclic ring or a 5        or 6-membered heteroaryl ring, wherein each 5 or 6-membered        heteroaryl ring or 4 to 7-membered heterocyclic ring contains up        to 4 ring heteroatoms independently selected from N, O and S;        and wherein each said phenyl, each of said benzyl, each said        C₃₋₈ cycloalkyl group, each said 4 to 7-membered heterocyclic        ring and each 5 or 6-membered heteroaryl ring is optionally and        independently substituted with up to 3 instances of R^(11b);        each R¹¹ is independently selected from halogen, oxo, C₁₋₆        alkyl, —CN, —OR¹², —COR¹², —C(O)OR¹², —C(O)N(R¹²)₂,        —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)₂, —N(R¹²)₂,        —SO₂R¹², —SO₂N(R¹²)₂ or —N(R¹²)SO₂R¹²; wherein each of said C₁₋₆        alkyl is optionally and independently substituted by up to 6        instances of fluoro and/or 3 instances of R¹²;        each R^(11a) is independently selected from halogen, oxo, C₁₋₆        alkyl, —CN, —OR¹², —COR¹², —C(O)OR¹², —C(O)N(R¹²)₂,        —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)₂, —N(R¹²)₂,        —SO₂R¹², —SO₂N(R¹²)₂ or —N(R¹²)SO₂R¹²; wherein each of said C₁₋₆        alkyl is optionally and independently substituted by up to 6        instances of fluoro and/or 3 instances of R¹²; and        each R^(11b) is independently selected from halogen, C₁₋₆ alkyl,        oxo, —CN, —OR¹², —COR¹², —C(O)OR¹², —C(O)N(R¹²)₂,        —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)₂, —N(R¹²)₂,        —SO₂R¹², —SO₂N(R¹²)₂ or —N(R¹²)SO₂R¹²; wherein each of said C₁₋₆        alkyl is optionally and independently substituted by up to 6        instances of fluoro and/or 3 instances of R¹²;        each R¹² is selected from hydrogen, a C₁₋₆ alkyl, phenyl,        benzyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclic        ring or a 5 or 6-membered heteroaryl ring, wherein each 5 or        6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring        contains up to 4 ring heteroatoms independently selected from N,        O and S; and wherein each of said C₁₋₆ alkyl, each said phenyl,        each said benzyl, each said C₃₋₈ cycloalkyl group, each said 4        to 7-membered heterocyclic ring and each 5 or 6-membered        heteroaryl ring is optionally and independently substituted with        up to 3 instances of halogen, C₁₋₄ alkyl, C₁₋₄ (fluoroalkyl),        —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —CONH₂,        —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ fluoroalkyl) or oxo.        R^(C) is either        i) a ring C; or        ii) is selected from halogen, —CN, C₁₋₆ alkyl, —(C₁₋₆        alkyl)-R^(N), —COR⁷, —C(O)OR⁷, —C(O)N(R⁷)₂, —N(R⁷)C(O)R⁷,        —N(R⁷)C(O)OR⁷, —N(R⁷)C(O)N(R⁷)₂, —N(R⁷)₂, —SO₂R⁷, —SO₂N(R⁷)₂,        —C(O)N(R⁷)SO₂R⁷, —SO₂N(R⁷)COOR⁷, —SO₂N(R⁷)C(O)R⁷ or —N(R⁷)SO₂R⁷;        wherein each said C₁₋₆ alkyl, each C₁₋₆ alkyl portion of said        —(C₁₋₆ alkyl)-R^(N), is optionally and independently substituted        with up to 6 instances of fluoro and up to 2 instances of —CN,        —OR⁸, oxo, —N(R⁸)₂, —N(R⁸)C(O)R⁸, —N(R⁸)C(O)OR⁸,        —N(R⁸)C(O)N(R⁸)₂, —SO₂R⁸, —SO₂N(R⁸)₂, —NHOR⁸, —SO₂N(R⁸)COOR⁸,        —SO₂N(R⁸)C(O)R⁸, —N(R⁸)SO₂R⁸;        wherein each R⁷ is independently selected from hydrogen, C₁₋₆        alkyl, C₁₋₆ fluoroalkyl, a C₃₋₈ cycloalkyl ring, phenyl, a 4 to        7-membered heterocyclic ring or a 5 or 6-membered heteroaryl        ring; wherein each of said 5 or 6-membered heteroaryl ring or 4        to 7-membered heterocyclic ring contains up to 4 ring        heteroatoms independently selected from N, O and S; and wherein        each of said C₁₋₆ alkyl, each of said phenyl, each of said C₃₋₈        cycloalkyl group, each of said 4 to 7-membered heterocyclic ring        and each of said 5 or 6-membered heteroaryl ring is optionally        and independently substituted with up to 3 instances of halogen,        C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN,        —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or        oxo;        each R⁸ is independently selected from hydrogen, C₁₋₆ alkyl,        C₁₋₆ fluoroalkyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered        heterocyclic ring or a 5 or 6-membered heteroaryl ring; wherein        each of said 5 or 6-membered heteroaryl ring or 4 to 7-membered        heterocyclic ring contains up to 4 ring heteroatoms        independently selected from N, O and S; and wherein each of said        C₁₋₆ alkyl, each of said phenyl, each of said C₃₋₈ cycloalkyl        group, each of said 4 to 7-membered heterocyclic ring and each        of said 5 or 6-membered heteroaryl ring is optionally and        independently substituted with up to 3 instances of halogen,        C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN,        —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄haloalkyl) or        oxo        each R^(N) is independently selected from a phenyl ring, a        monocyclic 5 or 6-membered heteroaryl ring, a monocyclic C₃₋₆        cycloaliphatic ring, or a monocyclic 4 to 6-membered        heterocycle; wherein said monocyclic 5 or 6-membered heteroaryl        ring or said monocyclic 4 to 6-membered heterocycle contain        between 1 and 4 heteroatoms selected from N, O or S; wherein        said monocyclic 5 or 6-membered heteroaryl ring is not a        1,3,5-triazinyl ring; and wherein said phenyl, said monocyclic 5        to 6-membered heteroaryl ring, said monocyclic C₃₋₆        cycloaliphatic ring, or said monocyclic 4 to 6-membered        heterocycle is optionally and independently substituted with up        to 6 instances of fluoro and/or up to 3 instances of J^(M);        each J^(M) is independently selected from —CN, a C₁₋₆ aliphatic,        —OR^(M), —SR^(M), —N(R^(M))₂, a C₃₋₈ cycloaliphatic ring or a 4        to 8-membered heterocyclic ring; wherein said 4 to 8-membered        heterocyclic ring contains 1 or 2 heteroatoms independently        selected from N, O or S; wherein each said C₁₋₆ aliphatic, each        said C₃₋₈ cycloaliphatic ring and each said 4 to 8-membered        heterocyclic ring, is optionally and independently substituted        with up to 3 instances of R^(7c);        each R^(M) is independently selected from hydrogen, a C₁₋₆        aliphatic, a C₃₋₈ cycloaliphatic ring or a 4 to 8-membered        heterocyclic ring; wherein each said 4 to 8-membered        heterocyclic ring contains between 1 and 3 heteroatoms        independently selected from O, N or S; and wherein        ring C is a phenyl ring, a monocyclic 5 or 6-membered heteroaryl        ring, a bicyclic 8 to 10-membered heteroaryl ring, a monocyclic        3 to 10-membered cycloaliphatic ring, or a monocyclic 4 to        10-membered heterocycle; wherein said monocyclic 5 or 6-membered        heteroaryl ring, said bicyclic 8 to 10-membered heteroaryl ring,        or said monocyclic 4 to 10-membered heterocycle contain between        1 and 4 heteroatoms selected from N, O or S; wherein said        monocyclic 5 or 6-membered heteroaryl ring is not a        1,3,5-triazinyl ring; and wherein said phenyl, monocyclic 5 to        6-membered heteroaryl ring, bicyclic 8 to 10-membered heteroaryl        ring, monocyclic 3 to 10-membered cycloaliphatic ring, or        monocyclic 4 to 10-membered heterocycle is optionally and        independently substituted with up to p instances of J^(C)′;        wherein p is 0 or an integer selected from 1 to 3.        each J^(C)′ is independently selected from halogen, —CN, —NO₂, a        C₁₋₆ aliphatic, —OR^(H), —SR^(H), —N(R^(H))₂, a C₃₋₈        cycloaliphatic ring or a 4 to 8-membered heterocyclic ring;        wherein said 4 to 8-membered heterocyclic ring contains 1 or 2        heteroatoms independently selected from N, O or S; wherein each        said C₁₋₆ aliphatic, each said C₃₋₈ cycloaliphatic ring and each        said 4 to 8-membered heterocyclic ring, is optionally and        independently substituted with up to 3 instances of R^(7d); or        alternatively, two J^(C)′ groups attached to two vicinal ring C        atoms, taken together with said two vicinal ring C atoms, form a        5 to 7-membered heterocycle that is a new ring fused to ring C;        wherein said 5 to 7-membered heterocycle contains from 1 to 2        heteroatoms independently selected from N, O or S;        each R^(H) is independently selected from hydrogen, a C₁₋₆        aliphatic, a C₃₋₈ cycloaliphatic ring or a 4 to 8-membered        heterocyclic ring; wherein each said 4 to 8-membered        heterocyclic ring contains between 1 and 3 heteroatoms        independently selected from O, N or S; alternatively, two        instances of R^(H) linked to the same nitrogen atom of        —N(R^(H))₂, together with said nitrogen atom of —N(R^(H))₂, form        a 4 to 8-membered heterocyclic ring or a 5-membered heteroaryl        ring; wherein each said 4 to 8-membered heterocyclic ring and        each said 5-membered heteroaryl ring optionally contains up to 2        additional heteroatoms independently selected from N, O or S;        each R^(7c) is independently selected from hydrogen, halogen,        —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl ring,        —OR^(8b), —SR^(8b), —N(R^(8b))₂, —C(O)O(C₁₋₄ alkyl), —C(O)OH,        —NR(CO)CO(C₁₋₄ alkyl) or an oxo group; wherein each said        cycloalkyl group is optionally and independently substituted        with up to 3 instances of halogen;        each R^(7d) is independently selected from hydrogen, halogen,        —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl ring,        —OR^(8c), —SR^(8c), —N(R^(8c))₂, or an oxo group; wherein each        said cycloalkyl group is optionally and independently        substituted with up to 3 instances of halogen;        each R^(8b) is independently selected from hydrogen, C₁₋₆ alkyl,        C₁₋₆ fluoroalkyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered        heterocyclic ring or a 5 or 6-membered heteroaryl ring; wherein        each of said 5 or 6-membered heteroaryl ring or 4 to 7-membered        heterocyclic ring contains up to 4 ring heteroatoms        independently selected from N, O and S; and wherein each of said        C₁₋₆ alkyl, each of said phenyl, each of said C₃₋₈ cycloalkyl        group, each of said 4 to 7-membered heterocyclic ring and each        of said 5 or 6-membered heteroaryl ring is optionally and        independently substituted with up to 3 instances of halogen,        C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN,        —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or        oxo;        each R^(8c) is independently selected from hydrogen, C₁₋₆ alkyl,        C₁₋₆ fluoroalkyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered        heterocyclic ring or a 5 or 6-membered heteroaryl ring; wherein        each of said 5 or 6-membered heteroaryl ring or 4 to 7-membered        heterocyclic ring contains up to 4 ring heteroatoms        independently selected from N, O and S; and wherein each of said        C₁₋₆ alkyl, each of said phenyl, each of said C₃₋₈ cycloalkyl        group, each of said 4 to 7-membered heterocyclic ring and each        of said 5 or 6-membered heteroaryl ring is optionally and        independently substituted with up to 3 instances of halogen,        C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN,        —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or        oxo;        provided that the compound is not a compound depicted below:

wherein J^(D) is either an ethylene or —N(Me)₂; J^(A) is either hydrogenor methyl; and J^(B) is either fluoro or C₁₋₂ alkoxy.

The present invention is also directed to compounds according to FormulaI, or pharmaceutically acceptable salts thereof,

-   wherein:-   X is selected from N, CH, C(C₁₋₄ alkyl), C(C₁₋₄haloalkyl), CCl and    CF;-   ring B is a phenyl or a 6-membered heteroaryl ring containing 1 or 2    ring nitrogen atoms, or ring B is a thiophene;-   n is 0 or an integer selected from 1 to 3;-   each J^(B) is independently selected from halogen, —CN, a C₁₋₆    aliphatic, —OR^(B) or a C₃₋₈ cycloaliphatic ring; wherein each of    said C₁₋₆ aliphatic and each of said C₃₋₈ cycloaliphatic group is    optionally substituted with up to 3 instances of halogen;-   each R^(B) is independently selected from hydrogen, a C₁₋₆ aliphatic    or a C₃₋₈ cycloaliphatic ring; wherein each of said R^(B) that is a    C₁₋₆ aliphatic and each of said R^(B) that is a C₃₋₈ cycloaliphatic    ring is optionally substituted with up to 3 instances of halogen;    J^(A) is selected from hydrogen, halogen, methyl, methoxy,    trifluoromethyl, trifluoromethoxy or —NR^(a)R^(b), wherein R^(a) and    R^(b) are each independently selected from hydrogen, C₁₋₆ alkyl or a    3-6 cycloalkyl ring;-   J^(D) is absent or selected from halogen, —CN, —CF₃, methoxy,    trifluoromethoxy, nitro, amino or methyl;-   R¹ and R², together with the nitrogen atom to which they are    attached, form a 4 to 8-membered heterocyclic ring or 5 or    6-membered heteroaryl ring; wherein said 4 to 8-membered    heterocyclic ring or 5 or 6-membered heteroaryl ring optionally    contains in addition to the nitrogen atom up to 3 ring heteroatoms    independently selected from N, O or S, and is optionally substituted    by up to 5 instances of R⁵; or-   alternatively, R¹ and R² are each independently selected from    hydrogen, C₁₋₆ alkyl, a C₃₋₈ cycloalkyl ring, a 4 to 8-membered    heterocyclic ring, a 5 or 6-membered heteroaryl or a C₁₋₆    alkyl-R^(Y); wherein each of said 4 to 8-membered heterocyclic ring    and each of said 5 or 6-membered heteroaryl ring contains up to 3    ring heteroatoms independently selected from N, O and S; and wherein    each of said C₁₋₆ alkyl, C₃₋₈ cycloalkyl ring, 4 to 8-membered    heterocyclic ring group, 5 or 6-membered heteroaryl and the C₁₋₆    alkyl portion of said C₁₋₆ alkyl-R^(Y) is optionally and    independently substituted with up to 5 instances of R^(5a); provided    that R¹ and R² are never simultaneously hydrogen; and provided than    when X is one of CH, C(C₁₋₄ alkyl), C(C₁₋₄ haloalkyl), CCl or CF,    one of R¹ and R² is not a pyridine or a pyrimidine; or-   alternatively, J^(D) and one of R¹ or R² can form a 5-6 membered    heterocyclic ring containing up to two heteroatoms selected from O,    N and S and optionally substituted with up to 3 instances of oxo or    —(Y)—R⁹;-   wherein Y is either absent or is a linkage in the form of a C₁₋₆    alkyl chain, optionally substituted by up to 6 instances of fluoro;    each R⁹ is independently selected from hydrogen, fluoro, —CN, —OR¹⁰,    —SR¹⁰, —COR¹⁰, —OC(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂,    —C(O)N(R¹⁰)SO₂R¹⁰, —N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)C(O)OR¹⁰,    —N(R¹⁰)C(O)N(R¹⁰)₂, —N(R¹⁰)₂, —SO₂R¹⁰, —SO₂N(R¹⁰)₂,    —SO₂N(R¹⁰)COOR¹⁰, —SO₂N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)SO₂R¹⁰, —(C═O)NHOR¹⁰, a    C₃₋₆ cycloalkyl ring, a 4-8-membered heterocyclic ring or a 5-6    membered heteroaryl ring; wherein each said 4 to 8-membered    heterocyclic ring or 5 to 6-membered heteroaromatic ring contains up    to 4 ring heteroatoms independently selected from N, O or S; and    wherein each of said C₃₋₆ cycloalkyl rings, each of said 4 to    8-membered heterocyclic rings and each of said 5 to 6-membered    heteroaromatic rings is optionally substituted with up to 3    instances of R¹¹;-   each R¹¹ is independently selected from halogen, C₁₋₆ alkyl, —CN,    —OR¹², —SR¹², —COR¹², —OC(O)R¹², —C(O)OR¹², —C(O)N(R¹²)₂,    —C(O)N(R¹²)SO₂R¹², —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,    —N(R¹²)C(O)N(R¹²)₂, —N(R¹²)₂, —SO₂R¹², —SO₂N(R¹²)₂,    —SO₂N(R¹²)COOR¹², —SO₂N(R¹²)C(O)R¹², —N(R¹²)SO₂R¹² and —N═OR¹²;    wherein each of said C₁₋₆ alkyl is optionally and independently    substituted by up to 3 instances of fluoro, —OH, —O(C₁₋₄ alkyl),    phenyl and —O(C₁₋₄ fluoroalkyl)-   wherein each R¹⁰ is independently selected from hydrogen, a C₁₋₆    alkyl, phenyl, benzyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered    heterocyclic ring or a 5 or 6-membered heteroaryl ring, wherein each    5 or 6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring    contains up to 4 ring heteroatoms independently selected from N, O    and S; and wherein each of said C₁₋₆ alkyl, each said phenyl, each    said benzyl, each said C₃₋₈ cycloalkyl group, each said 4 to    7-membered heterocyclic ring and each 5 or 6-membered heteroaryl    ring is optionally and independently substituted with up to 3    instances of halogen, C₁₋₄ alkyl, C₁₋₄ (fluoroalkyl), —OH, —NH₂,    —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —COO(C₁₋₄ alkyl),    —O(C₁₋₄ alkyl), —O(C₁₋₄ fluoroalkyl) or oxo; and-   wherein each R¹² is independently selected from hydrogen, a C₁₋₆    alkyl, phenyl, benzyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered    heterocyclic ring or a 5 or 6-membered heteroaryl ring, wherein each    5 or 6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring    contains up to 4 ring heteroatoms independently selected from N, O    and S; and wherein each of said C₁₋₆ alkyl, each said phenyl, each    said benzyl, each said C₃₋₈ cycloalkyl group, each said 4 to    7-membered heterocyclic ring and each 5 or 6-membered heteroaryl    ring is optionally and independently substituted with up to 3    instances of halogen, C₁₋₄ alkyl, C₁₋₄ (fluoroalkyl), —OH, —NH₂,    —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —COO(C₁₋₄ alkyl),    —O(C₁₋₄ alkyl), —O(C₁₋₄ fluoroalkyl) or oxo;-   R^(Y) is selected from a C₃₋₈ cycloalkyl ring, a 4 to 8-membered    heterocyclic ring, phenyl, or a 5 to 6-membered heteroaromatic ring;    wherein each of said 4 to 8-membered heterocyclic ring or 5 to    6-membered heteroaromatic ring contains up to 4 ring heteroatoms    independently selected from N, O or S; and wherein each of said C₃₋₈    cycloalkyl ring, each of said 4 to 8-membered heterocyclic ring,    each of said phenyl, and each of said 5 to 6-membered heteroaromatic    ring is optionally substituted with up to 5 instances of-   each R^(5c) is independently selected from halogen, —CN, C₁₋₆ alkyl,    —OR^(6b), —SR^(6b), —COR^(6b), —OC(O)R^(6b), —C(O)OR^(6b),    —C(O)N(R^(6b))₂, —C(O)N(R^(6b))SO₂R^(6b), —N(R^(6b))C(O)R^(6b),    —N(R^(6b))C(O)OR^(6b), —N(R^(6b))C(O)N(R^(6b))₂, —N(R^(6b))₂,    —SO₂R^(6b), —SO₂N(R^(6b))₂, —SO₂N(R^(6b))COOR^(6b),    —SO₂N(R^(6b))C(O)R^(6b), —N(R^(6b))SO₂R^(6b), —(C═O)NHOR^(6b), a    C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclic ring, a 5 or    6-membered heteroaryl ring, phenyl, benzyl, an oxo group, or a    bicyclic group; wherein each of said 5 or 6-membered heteroaryl ring    and each of said 4 to 7-membered heterocyclic ring contains up to 4    ring heteroatoms independently selected from N, O and S; and wherein    each of said C₁₋₆ alkyl, each of said C₃₋₈ cycloalkyl ring, each of    said 4 to 7-membered heterocyclic ring, each of said 5 or 6-membered    heteroaryl ring, each of said benzyl and each of said phenyl group    is optionally and independently substituted with up to 3 instances    of halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂,    —CN, —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or    oxo; wherein said bicyclic group contains a first ring and a second    ring in a fused or bridged relationship, said first ring is a 4 to    7-membered heterocyclic ring, a 5 or 6-membered heteroaryl ring,    phenyl or benzyl, and said second ring is a phenyl ring or a 5 or    6-membered heteroaryl ring containing up to 3 ring heteroatoms    selected from N, O or S; and wherein said bicyclic group is    optionally and independently substituted by up to six instances of    halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂,    —CN, —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or    oxo;-   each R^(6b) is independently selected from hydrogen, a C₁₋₆ alkyl,    phenyl, benzyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered    heterocyclic ring or a 5 or 6-membered heteroaryl ring, wherein each    5 or 6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring    contains up to 4 ring heteroatoms independently selected from N, O    and S; and wherein each of said C₁₋₆ alkyl, each said phenyl, each    said benzyl, each said C₃₋₈ cycloalkyl group, each said 4 to    7-membered heterocyclic ring and each 5 or 6-membered heteroaryl    ring is optionally and independently substituted with up to 3    instances of halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl),    —N(C₁₋₄ alkyl)₂, —CN, —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl),    —O(C₁₋₄ haloalkyl) or oxo; or-   two instances of R^(5c) attached to the same or different ring atoms    of R^(Y), together with said ring atom or atoms, may form a C₃₋₈    cycloalkyl ring, a 4 to 6-membered heterocyclic ring; a phenyl or a    5 or 6-membered heteroaryl ring, resulting in a bicyclic system    wherein the two rings are in a spiro, fused or bridged relationship,    wherein said 4 to 6-membered heterocycle or said 5 or 6-membered    heteroaryl ring contains up to three heteroatoms independently    selected from N, O or S; and wherein said C₃₋₈ cycloalkyl ring, 4 to    6-membered heterocyclic ring, phenyl or a 5 or 6-membered heteroaryl    ring is optionally and independently substituted by up to 3    instances of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄    haloalkoxy, oxo, —C(O)O(C₁₋₄ alkyl), —C(O)OH, —NR″(CO)CO(C₁₋₄    alkyl), —OH or halogen; wherein R″ is hydrogen or a C₁₋₂ alkyl;-   each R^(5a) is independently selected from halogen, —CN, C₁₋₆ alkyl,    —OR^(6a), —SR^(6a), —COR^(6a), —OC(O)R^(6a), —C(O)OR^(6a),    —C(O)N(R^(6a))₂, —C(O)N(R^(6a))SO₂R^(6a), —N(R^(6a))C(O)R^(6a),    —N(R^(6a))C(O)OR^(6a), —N(R^(6a))C(O)N(R^(6a))₂, —N(R^(6a))₂,    —SO₂R^(6a), —SO₂N(R^(6a))₂, —SO₂N(R^(6a))COOR^(6a),    —SO₂N(R^(6a))C(O)R^(6a), —N(R^(6a))SO₂R^(6a), —(C═O)NHOR^(6a), a    C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclic ring, a 5 or    6-membered heteroaryl ring, phenyl, benzyl, an oxo group or a    bicyclic group; wherein each 5 or 6-membered heteroaryl ring or 4 to    7-membered heterocyclic ring contains up to 4 ring heteroatoms    independently selected from N, O and S, wherein each of said C₁₋₆    alkyl, C₃₋₈ cycloalkyl ring, 4 to 7-membered heterocyclic ring, 5 or    6-membered heteroaryl ring, benzyl or phenyl group is optionally and    independently substituted with up to 3 instances of halogen, C₁₋₄    alkyl, C₁₋₄ haloalkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂,    —CN, —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or    oxo; wherein said bicyclic group contains ring one and ring two in a    fused or bridged relationship, said ring one is a 4 to 7-membered    heterocyclic ring, a 5 or 6-membered heteroaryl ring, phenyl or    benzyl, and said ring two is a phenyl ring or a 5 or 6-membered    heteroaryl ring containing up to 3 ring heteroatoms selected from N,    O or S; and wherein said bicyclic group is optionally and    independently substituted by up to six instances of halogen, C₁₋₄    alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH,    —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo;    each R^(6a) is independently selected from hydrogen, a C₁₋₆ alkyl,    phenyl, benzyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered    heterocyclic ring or a 5 or 6-membered heteroaryl ring, wherein each    of said C₁₋₆ alkyl, each of said phenyl, each of said benzyl, each    of said C₃₋₈ cycloalkyl group, each of said 4 to 7-membered    heterocyclic ring and each of said 5 or 6-membered heteroaryl ring    is optionally and independently substituted with up to 3 instances    of halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂,    —CN, —COOH, —C(O)NH₂, —C(O)N(C₁₋₆ alkyl)₂, —C(O)NH(C₁₋₆ alkyl),    —C(O)N(C₁₋₆ haloalkyl)₂, —C(O)NH(C₁₋₆ haloalkyl), C(O)N(C₁₋₆    alkyl)(C₁₋₆ haloalkyl), —COO(C₁₋₆ alkyl), —COO(C₁₋₆ haloalkyl),    —O(C₁₋₄ alkyl), —O(C₁₋₄haloalkyl) or oxo, wherein each of said 5 or    6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring    contains up to 4 ring heteroatoms independently selected from N, O    and S; or-   when one of R¹ or R² is the C₃₋₈ cycloalkyl ring, 4 to 8-membered    heterocyclic ring or 5 or 6-membered heteroaryl substituted with up    to 5 instances of R^(5a), two of the instances of R^(5a) attached to    the same or different ring atoms of said R¹ or R², together with    said atom or atoms, may optionally form a C₃₋₈ cycloalkyl ring, a 4    to 6-membered heterocyclic ring, a phenyl or a 5 or 6-membered    heterocyclic ring, resulting in a bicyclic system wherein the two    rings are in a spiro, fused or bridged relationship, wherein said 4    to 6-membered heterocycle or said 5 or 6-membered heterocyclic ring    contains up to two ring heteroatoms independently selected from N, O    or S; and wherein said C₃₋₈ cycloalkyl ring, 4 to 6-membered    heterocyclic ring, phenyl or 5 or 6-membered heterocyclic ring is    optionally substituted by up to 2 instances of C₁₋₄ alkyl, C₁₋₄    haloalkyl, oxo, —(CO)CO(C₁₋₄ alkyl), —NR′(CO)CO(C₁₋₄ alkyl) or    halogen; wherein R′ is hydrogen or a C₁₋₂ alkyl;-   each R⁵ is independently selected from halogen, —CN, C₁₋₆ alkyl,    —OR⁶, —SR⁶, —COR⁶, —OC(O)R⁶, —C(O)OR⁶, —C(O)N(R⁶)₂,    —C(O)N(R⁶)SO₂R⁶,—N(R⁶)C(O)R⁶, —N(R⁶)C(O)OR⁶, —N(R⁶)C(O)N(R⁶)₂,    —N(R⁶)₂, —SO₂R⁶, —SO₂N(R⁶)₂, —SO₂N(R⁶)COOR⁶, —SO₂N(R⁶)C(O)R⁶,    —N(R⁶)SO₂R⁶, —(C═O)NHOR⁶, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered    heterocyclic ring, a 5 or 6-membered heteroaryl ring, phenyl,    benzyl, an oxo group or a bicyclic group; wherein each of said 5 or    6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring    contains up to 4 ring heteroatoms independently selected from N, O    and S; and wherein each of said C₁₋₆ alkyl, C₃₋₈ cycloalkyl ring, 4    to 7-membered heterocyclic ring, 5 or 6-membered heteroaryl ring,    benzyl or phenyl group is optionally and independently substituted    with up to 3 instances of halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄    alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄    alkyl), —O(C₁₋₄ haloalkyl) or oxo; wherein said bicyclic group    contains ring one and ring two in a fused or bridged relationship,    said ring one is a 4 to 7-membered heterocyclic ring, a 5 or    6-membered heteroaryl ring, phenyl or benzyl, and said ring two is a    phenyl ring or a 5 or 6-membered heteroaryl ring containing up to 3    ring heteroatoms selected from N, O or S; and wherein said bicyclic    group is optionally and independently substituted by up to six    instances of halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl),    —N(C₁₋₄ alkyl)₂, —CN, —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl),    —O(C₁₋₄ haloalkyl) or oxo;-   each R⁶ is independently selected from hydrogen, a C₁₋₆ alkyl,    phenyl, benzyl, a C₃₋₈ cycloalkyl ring or a 4 to 7-membered    heterocyclic ring, a 5 or 6-membered heteroaryl ring; wherein each    of said 5 or 6-membered heteroaryl ring or 4 to 7-membered    heterocyclic ring contains up to 4 ring heteroatoms independently    selected from N, O and S; and wherein each of said C₁₋₆ alkyl, each    of said phenyl, each of said benzyl, each of said C₃₋₈ cycloalkyl    group, each of said 4 to 7-membered heterocyclic ring and each of    said 5 or 6-membered heteroaryl ring is optionally and independently    substituted with up to 3 instances of halogen, C₁₋₄ alkyl, —OH,    —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —COO(C₁₋₄    alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo; or-   when R¹ and R² attached to the nitrogen atom form the 4 to    8-membered heterocyclic ring or 5 or 6-membered heteroaryl ring    substituted with up to 5 instances of R⁵, two of the instances of R⁵    attached to the same or different atoms of said ring, together with    said atom or atoms, may optionally form a C₃₋₈ cycloalkyl ring, a 4    to 6-membered heterocyclic ring; a phenyl or a 5 or 6-membered    heteroaryl ring, resulting in a bicyclic system wherein the two    rings of the bicyclic system are in a spiro, fused or bridged    relationship, wherein said 4 to 6-membered heterocycle or said 5 or    6-membered heteroaryl ring contains up to three ring heteroatoms    independently selected from N, O or S; and wherein said C₃₋₈    cycloalkyl ring, 4 to 6-membered heterocyclic ring, phenyl or 5 or    6-membered heteroaryl ring is optionally and independently    substituted by up to 3 instances of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄    alkoxy, C₁₋₄haloalkoxy, oxo, —C(O)O(C₁₋₄ alkyl), —C(O)OH,    —NR(CO)CO(C₁₋₄ alkyl), —OH or halogen; wherein R is hydrogen or a    C₁₋₂ alkyl;-   p is an integer selected from 0, 1 or 2;-   ring C is a monocyclic 5-membered heteroaryl ring containing up to 4    ring heteroatoms selected from N, O or S; wherein said monocyclic    5-membered heteroaryl ring is not a 1,3,5-triazinyl ring;-   each J^(C) is independently selected from halogen or a C₁₋₄    aliphatic optionally and independently substituted by up to 3    instances of C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, oxo, —C(O)O(C₁₋₄ alkyl),    —C(O)OH, —NR(CO)CO(C₁₋₄ alkyl), —OH or halogen.

The invention is also directed to a pharmaceutical compositioncomprising a compound according to Formula I or Formula I′, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient or carrier. The invention is alsodirected to a pharmaceutical formulation or dosage form comprising thepharmaceutical composition.

The invention also provides a method of treating or preventing adisease, health condition or disorder in a subject in need thereof,comprising administering, alone or in combination therapy, atherapeutically effective amount of a compound of Formula I or FormulaI′ or a pharmaceutically acceptable salt thereof to the subject; whereinthe disease, health condition or disorder is a peripheral, pulmonary,hepatic, kidney, cardiac or cerebral vascular/endothelial disorder orcondition, a urogenital-gynecological or sexual disorder or condition, athromboembolic disease, a fibrotic disorder, a pulmonary or respiratorydisorder, renal or hepatic disorder, ocular disorder, hearing disorder,CNS disorder, circulation disorder, topical or skin disorder, metabolicdisorder, atherosclerosis, wound healing or a lipid related disorderthat benefits from sGC stimulation or from an increase in theconcentration of NO or cGMP.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulae. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments.Rather, the invention is intended to cover all alternatives,modifications and equivalents that may be included within the scope ofthe present invention as defined by the claims. The present invention isnot limited to the methods and materials described herein but includeany methods and materials similar or equivalent to those describedherein that could be used in the practice of the present invention. Inthe event that one or more of the incorporated literature references,patents or similar materials differ from or contradict this application,including but not limited to defined terms, term usage, describedtechniques or the like, this application controls.

Definitions and General Terminology

For purposes of this disclosure, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version, and theHandbook of Chemistry and Physics, 75^(th) Ed. 1994. Additionally,general principles of organic chemistry are described in “OrganicChemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999,and “March's Advanced Organic Chemistry”, 5^(th) Ed., Smith, M. B. andMarch, J., eds. John Wiley & Sons, New York: 2001, which are hereinincorporated by reference in their entirety.

As described herein, compounds of Formula I may be optionallysubstituted with one or more substituents, such as illustrated generallybelow, or as exemplified by particular classes, subclasses and speciesof the invention. The phrase “optionally substituted” is usedinterchangeably with the phrase “substituted or unsubstituted.” Ingeneral, the term “substituted” refers to the replacement of one or morehydrogen radicals in a given structure with the radical of a specifiedsubstituent. Unless otherwise indicated, an optionally substituted groupmay have a substituent at each substitutable position of the group. Whenmore than one position in a given structure can be substituted with morethan one substituent selected from a specified group, the substituentmay be either the same or different at each position unless otherwisespecified. As will be apparent to one of ordinary skill in the art,groups such as —H, halogen, —NO₂, —CN, —OH, —NH₂ or —OCF₃ would not besubstitutable groups.

The phrase “up to”, as used herein, refers to zero or any integer numberthat is equal to or less than the number following the phrase. Forexample, “up to 3” means any one of 0, 1, 2, or 3. As described herein,a specified number range of atoms includes any integer therein. Forexample, a group having from 1-4 atoms could have 1, 2, 3 or 4 atoms.When any variable occurs more than one time at any position, itsdefinition on each occurrence is independent from every otheroccurrence.

Selection of substituents and combinations envisioned by this disclosureare only those that result in the formation of stable or chemicallyfeasible compounds. Such choices and combinations will be apparent tothose of ordinary skill in the art and may be determined without undueexperimentation. The term “stable”, as used herein, refers to compoundsthat are not substantially altered when subjected to conditions to allowfor their production, detection, and, in some embodiments, theirrecovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound is one that isnot substantially altered when kept at a temperature of 25° C. or less,in the absence of moisture or other chemically reactive conditions, forat least a week. A chemically feasible compound is a compound that canbe prepared by a person skilled in the art based on the disclosuresherein supplemented, if necessary, relevant knowledge of the art.

A compound, such as the compounds of Formula I or other compounds hereindisclosed, may be present in its free form (e.g. an amorphous form, or acrystalline form or a polymorph). Under certain conditions, compoundsmay also form co-forms. As used herein, the term co-form is synonymouswith the term multi-component crystalline form. When one of thecomponents in the co-form has clearly transferred a proton to the othercomponent, the resulting co-form is referred to as a “salt”. Theformation of a salt is determined by how large the difference is in thepKas between the partners that form the mixture. For purposes of thisdisclosure, compounds include pharmaceutically acceptable salts, even ifthe term “pharmaceutically acceptable salts” is not explicitly noted.

Unless only one of the isomers is drawn or named specifically,structures depicted herein are also meant to include all stereoisomeric(e.g., enantiomeric, diastereomeric, atropoisomeric and cis-transisomeric) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Ra and Sa configurations foreach asymmetric axis, (Z) and (E) double bond configurations, and cisand trans conformational isomers. Therefore, single stereochemicalisomers as well as racemates, and mixtures of enantiomers,diastereomers, and cis-trans isomers (double bond or conformational) ofthe present compounds are within the scope of the present disclosure.Unless otherwise stated, all tautomeric forms of the compounds of thepresent disclosure are also within the scope of the invention. As anexample, a substituent drawn as below:

wherein R may be hydrogen, would include both compounds shown below:

The present disclosure also embraces isotopically-labeled compoundswhich are identical to those recited herein, but for the fact that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. All isotopes of any particular atom or element as specified arecontemplated within the scope of the compounds of the invention, andtheir uses. Exemplary isotopes that can be incorporated into compoundsof the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C,¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and¹²⁵I, respectively. Certain isotopically-labeled compounds of thepresent invention (e.g., those labeled with ³H and ¹⁴C) are useful incompound and/or substrate tissue distribution assays. Tritiated (i.e.,³H) and carbon-14 (i.e., ¹⁴C) isotopes are useful for their ease ofpreparation and detectability. Further, substitution with heavierisotopes such as deuterium (i.e., ²H) may afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements) and hence may bepreferred in some circumstances. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C, and ¹⁸F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds of the present invention can generally be prepared byfollowing procedures analogous to those disclosed in the Schemes and/orin the Examples herein below, by substituting an isotopically labeledreagent for a non-isotopically labeled reagent.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation. Unless otherwise specified,aliphatic groups contain 1-20 aliphatic carbon atoms. In someembodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. Inother embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms.In still other embodiments, aliphatic groups contain 1-6 aliphaticcarbon atoms. In other embodiments, aliphatic groups contain 1-4aliphatic carbon atoms and in yet other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms. Suitable aliphatic groups include,but are not limited to, linear or branched, substituted or unsubstitutedalkyl, alkenyl, or alkynyl groups. Specific examples of aliphatic groupsinclude, but are not limited to: methyl, ethyl, propyl, butyl,isopropyl, isobutyl, vinyl, sec-butyl, tert-butyl, butenyl, propargyl,acetylene and the like. To be perfectly clear, the term “aliphaticchain” may be used interchangeably with the term “aliphatic” or“aliphatic group”.

The term “alkyl”, as used herein, refers to a saturated linear orbranched-chain monovalent hydrocarbon radical. Unless otherwisespecified, an alkyl group contains 1-20 carbon atoms (e.g., 1-20 carbonatoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1-4 carbonatoms or 1-3 carbon atoms). Examples of alkyl groups include, but arenot limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl and the like.

The term “alkenyl” refers to a linear or branched-chain monovalenthydrocarbon radical with at least one site of unsaturation, i.e., acarbon-carbon, sp² double bond, wherein the alkenyl radical includesradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations. Unless otherwise specified, an alkenyl groupcontains 2-20 carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms,2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms or 2-3 carbonatoms). Examples include, but are not limited to, vinyl, allyl and thelike.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbonradical with at least one site of unsaturation, i.e., a carbon-carbon sptriple bond. Unless otherwise specified, an alkynyl group contains 2-20carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms, 2-8 carbonatoms, 2-6 carbon atoms, 2-4 carbon atoms or 2-3 carbon atoms). Examplesinclude, but are not limited to, ethynyl, propynyl, and the like.

The term “carbocyclic” refers to a ring system formed only by carbon andhydrogen atoms. Unless otherwise specified, throughout this disclosure,carbocycle is used as a synonym of “non-aromatic carbocycle” or“cycloaliphatic”. In some instances the term can be used in the phrase“aromatic carbocycle”, and in this case it refers to an “aryl group” asdefined below.

The term “cycloaliphatic” (or “non-aromatic carbocycle”, “non-aromaticcarbocyclyl”, “non-aromatic carbocyclic”) refers to a cyclic hydrocarbonthat is completely saturated or that contains one or more units ofunsaturation but which is not aromatic, and which has a single point ofattachment to the rest of the molecule. Unless otherwise specified, acycloaliphatic group may be monocyclic, bicyclic, tricyclic, fused,spiro or bridged. In one embodiment, the term “cycloaliphatic” refers toa monocyclic C₃-C₁₂ hydrocarbon or a bicyclic C₇-C₁₂ hydrocarbon. Insome embodiments, any individual ring in a bicyclic or tricyclic ringsystem has 3-7 members. Suitable cycloaliphatic groups include, but arenot limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples ofaliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl,norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl,cyclododecyl, and the like.

The term “cycloaliphatic” also includes polycyclic ring systems in whichthe non-aromatic carbocyclic ring can be “fused” to one or more aromaticor non-aromatic carbocyclic or heterocyclic rings or combinationsthereof, as long as the radical or point of attachment is on thenon-aromatic carbocyclic ring.

“Cycloalkyl”, as used herein, refers to a ring system in which iscompletely saturated and which has a single point of attachment to therest of the molecule. Unless otherwise specified, a cycloalkyl group maybe monocyclic, bicyclic, tricyclic, fused, spiro or bridged. In oneembodiment, the term “cycloalkyl” refers to a monocyclic C₃-C₁₂saturated hydrocarbon or a bicyclic C₇-C₁₂ saturated hydrocarbon. Insome embodiments, any individual ring in a bicyclic or tricyclic ringsystem has 3-7 members. Suitable cycloalkyl groups include, but are notlimited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl,cyclodecyl, cycloundecyl, cyclododecyl, and the like.

“Heterocycle” (or “heterocyclyl” or “heterocyclic), as used herein,refers to a ring system in which one or more ring members are anindependently selected heteroatom, which is completely saturated or thatcontains one or more units of unsaturation but which is not aromatic,and which has a single point of attachment to the rest of the molecule.Unless otherwise specified, through this disclosure, heterocycle is usedas a synonym of “non-aromatic heterocycle”. In some instances the termcan be used in the phrase “aromatic heterocycle”, and in this case itrefers to a “heteroaryl group” as defined below. The term heterocyclealso includes fused, spiro or bridged heterocyclic ring systems. Unlessotherwise specified, a heterocycle may be monocyclic, bicyclic ortricyclic. In some embodiments, the heterocycle has 3-18 ring members inwhich one or more ring members is a heteroatom independently selectedfrom oxygen, sulfur or nitrogen, and each ring in the system contains 3to 7 ring members. In other embodiments, a heterocycle may be amonocycle having 3-7 ring members (2-6 carbon atoms and 1-4 heteroatoms)or a bicycle having 7-10 ring members (4-9 carbon atoms and 1-6heteroatoms). Examples of bicyclic heterocyclic ring systems include,but are not limited to: adamantanyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl.

As used herein, the term “heterocycle” also includes polycyclic ringsystems wherein the heterocyclic ring is fused with one or more aromaticor non-aromatic carbocyclic or heterocyclic rings, or with combinationsthereof, as long as the radical or point of attachment is on theheterocyclic ring.

Examples of heterocyclic rings include, but are not limited to, thefollowing monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl,2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino,3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino,4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl; and the followingbicycles: 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane,benzodithiane, and 1,3-dihydro-imidazol-2-one.

As used herein, the term “aryl” (as in “aryl ring” or “aryl group”),used alone or as part of a larger moiety, as in “aralkyl”, “aralkoxy”,“aryloxyalkyl”, refers to a carbocyclic ring system wherein at least onering in the system is aromatic and has a single point of attachment tothe rest of the molecule. Unless otherwise specified, an aryl group maybe monocyclic, bicyclic or tricyclic and contain 6-18 ring members. Theterm also includes polycyclic ring systems where the aryl ring is fusedwith one or more aromatic or non-aromatic carbocyclic or heterocyclicrings, or with combinations thereof, as long as the radical or point ofattachment is in the aryl ring. Examples of aryl rings include, but arenot limited to, phenyl, naphthyl, indanyl, indenyl, tetralin, fluorenyl,and anthracenyl.

The term “aralkyl” refers to a radical having an aryl ring substitutedwith an alkylene group, wherein the open end of the alkylene groupallows the aralkyl radical to bond to another part of the compound ofFormula I. The alkylene group is a bivalent, straight-chain or branched,saturated hydrocarbon group. As used herein, the term “C₇₋₁₂ aralkyl”means an aralkyl radical wherein the total number of carbon atoms in thearyl ring and the alkylene group combined is 7 to 12. Examples of“aralkyl” include, but not limited to, a phenyl ring substituted by aC₁₋₆ alkylene group, e.g., benzyl and phenylethyl, and a naphthyl groupsubstituted by a C₁₋₂ alkylene group.

The term “heteroaryl” (or “heteroaromatic” or “heteroaryl group” or“aromatic heterocycle”) used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy” refers to a ring system wherein atleast one ring in the system is aromatic and contains one or moreheteroatoms, wherein each ring in the system contains 3 to 7 ringmembers and which has a single point of attachment to the rest of themolecule. Unless otherwise specified, a heteroaryl ring system may bemonocyclic, bicyclic or tricyclic and have a total of five to fourteenring members. In one embodiment, all rings in a heteroaryl system arearomatic. Also included in this definition are heteroaryl radicals wherethe heteroaryl ring is fused with one or more aromatic or non-aromaticcarbocyclic or heterocyclic rings, or combinations thereof, as long asthe radical or point of attachment is in the heteroaryl ring. Bicyclic6, 5 heteroaromatic system, as used herein, for example, is a sixmembered heteroaromatic ring fused to a second five membered ringwherein the radical or point of attachment is on the six-membered ring.

Heteroaryl rings include, but are not limited to the followingmonocycles: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl,4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl(e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl(e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, andthe following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl,benzopyrazinyl, benzopyranonyl, indolyl (e.g., 2-indolyl), purinyl,quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), andisoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or4-isoquinolinyl).

As used herein, “cyclo” (or “cyclic”, or “cyclic moiety”) encompassesmono-, bi- and tri-cyclic ring systems including cycloaliphatic,heterocyclic, aryl or heteroaryl, each of which has been previouslydefined.

“Fused” bicyclic ring systems comprise two rings which share twoadjoining ring atoms.

“Bridged” bicyclic ring systems comprise two rings which share three orfour adjacent ring atoms. As used herein, the term “bridge” refers to anatom or a chain of atoms connecting two different parts of a molecule.The two atoms that are connected through the bridge (usually but notalways, two tertiary carbon atoms) are referred to as “bridgeheads”. Inaddition to the bridge, the two bridgeheads are connected by at leasttwo individual atoms or chains of atoms. Examples of bridged bicyclicring systems include, but are not limited to, adamantanyl, norbornanyl,bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl,bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. “Spiro” bicyclic ring systems shareonly one ring atom (usually a quaternary carbon atom) between the tworings.

The term “ring atom” refers to an atom such as C, N, O or S that is partof the ring of an aromatic ring, a cycloaliphatic ring, a heterocyclicor a heteroaryl ring. A “substitutable ring atom” is a ring carbon ornitrogen atom bonded to at least one hydrogen atom. The hydrogen can beoptionally replaced with a suitable substituent group. Thus, the term“substitutable ring atom” does not include ring nitrogen or carbon atomswhich are shared when two rings are fused. In addition, “substitutablering atom” does not include ring carbon or nitrogen atoms when thestructure depicts that they are already attached to one or more moietyother than hydrogen and no hydrogens are available for substitution.

“Heteroatom” refers to one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon, including any oxidized form of nitrogen, sulfur,phosphorus, or silicon, the quaternized form of any basic nitrogen, or asubstitutable nitrogen of a heterocyclic or heteroaryl ring, for exampleN (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl).

In some embodiments, two independent occurrences of a variable may betaken together with the atom(s) to which each variable is bound to forma 5-8-membered, heterocyclyl, aryl, or heteroaryl ring or a 3-8-memberedcycloaliphatic ring. Exemplary rings that are formed when twoindependent occurrences of a substituent are taken together with theatom(s) to which each variable is bound include, but are not limited tothe following: a) two independent occurrences of a substituent that arebound to the same atom and are taken together with that atom to form aring, where both occurrences of the substituent are taken together withthe atom to which they are bound to form a heterocyclyl, heteroaryl,cycloaliphatic or aryl ring, wherein the group is attached to the restof the molecule by a single point of attachment; and b) two independentoccurrences of a substituent that are bound to different atoms and aretaken together with both of those atoms to form a heterocyclyl,heteroaryl, cycloaliphatic or aryl ring, wherein the ring that is formedhas two points of attachment with the rest of the molecule. For example,where a phenyl group is substituted with two occurrences of —OR^(o) asin Formula D1:

these two occurrences of —OR^(o) are taken together with the carbonatoms to which they are bound to form a fused 6-membered oxygencontaining ring as in Formula D2:

It will be appreciated that a variety of other rings can be formed whentwo independent occurrences of a substituent are taken together with theatom(s) to which each substituent is bound and that the examplesdetailed above are not intended to be limiting.

In some embodiments, an alkyl or aliphatic chain can be optionallyinterrupted with another atom or group. This means that a methylene unitof the alkyl or aliphatic chain can optionally be replaced with saidother atom or group. Unless otherwise specified, the optionalreplacements form a chemically stable compound. Optional interruptionscan occur both within the chain and/or at either end of the chain; i.e.both at the point of attachment(s) to the rest of the molecule and/or atthe terminal end. Two optional replacements can also be adjacent to eachother within a chain so long as it results in a chemically stablecompound. Unless otherwise specified, if the replacement or interruptionoccurs at a terminal end of the chain, the replacement atom is bound toan H on the terminal end. For example, if —CH₂CH₂CH₃ were optionallyinterrupted with —O—, the resulting compound could be —OCH₂CH₃,—CH₂OCH₃, or —CH₂CH₂OH. In another example, if the divalent linker—CH₂CH₂CH₂— were optionally interrupted with —O—, the resulting compoundcould be —OCH₂CH₂—, —CH₂OCH₂—, or —CH₂CH₂O—. The optional replacementscan also completely replace all of the carbon atoms in a chain. Forexample, a C₃ aliphatic can be optionally replaced by —N(R′)—, —C(O)—,and —N(R′)— to form —N(R′)C(O)N(R′)— (a urea).

In general, the term “vicinal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to adjacent carbon atoms.

In general, the term “geminal” refers to the placement of substituentson a group that includes two or more carbon atoms, wherein thesubstituents are attached to the same carbon atom.

The terms “terminally” and “internally” refer to the location of a groupwithin a substituent. A group is terminal when the group is present atthe end of the substituent not further bonded to the rest of thechemical structure. Carboxyalkyl, i.e., R^(X)O(O)C-alkyl is an exampleof a carboxy group used terminally. A group is internal when the groupis present in the middle of a substituent at the end of the substituentbound to the rest of the chemical structure. Alkylcarboxy (e.g.,alkyl-C(O)O— or alkyl-O(CO)—) and alkylcarboxyaryl (e.g.,alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groupsused internally.

As described herein, a bond drawn from a substituent to the center ofone ring within a multiple-ring system (as shown below), representssubstitution of the substituent at any substitutable position in any ofthe rings within the multiple ring system. For example, formula D3represents possible substitution in any of the positions shown informula D4:

This also applies to multiple ring systems fused to optional ringsystems (which would be represented by dotted lines). For example, inFormula D5, X is an optional substituent both for ring A and ring B.

If, however, two rings in a multiple ring system each have differentsubstituents drawn from the center of each ring, then, unless otherwisespecified, each substituent only represents substitution on the ring towhich it is attached. For example, in Formula D6, Y is an optionalsubstituent for ring A only, and X is an optional substituent for ring Bonly.

As used herein, the terms “alkoxy” or “alkylthio” refer to an alkylgroup, as previously defined, attached to the molecule, or to anotherchain or ring, through an oxygen (“alkoxy” i.e., —O-alkyl) or a sulfur(“alkylthio” i.e., —S-alkyl) atom.

The terms C_(n-m) “alkoxyalkyl”, C_(n-m) “alkoxyalkenyl”, C_(n-m)“alkoxyaliphatic”, and C_(n-m) “alkoxyalkoxy” mean alkyl, alkenyl,aliphatic or alkoxy, as the case may be, substituted with one or morealkoxy groups, wherein the combined total number of carbons of the alkyland alkoxy groups, alkenyl and alkoxy groups, aliphatic and alkoxygroups or alkoxy and alkoxy groups, combined, as the case may be, isbetween the values of n and m. For example, a C₄₋₆ alkoxyalkyl has atotal of 4-6 carbons divided between the alkyl and alkoxy portion; e.g.it can be —CH₂OCH₂CH₂CH₃, —CH₂CH₂OCH₂CH₃ or —CH₂CH₂CH₂OCH₃.

When the moieties described in the preceding paragraph are optionallysubstituted, they can be substituted in either or both of the portionson either side of the oxygen or sulfur. For example, an optionallysubstituted C₄ alkoxyalkyl could be, for instance, —CH₂CH₂OCH₂(Me)CH₃ or—CH₂(OH)O CH₂CH₂CH₃; a C₅ alkoxyalkenyl could be, for instance, —CH═CHOCH₂CH₂CH₃ or —CH═CHCH₂OCH₂CH₃.

The terms aryloxy, arylthio, benzyloxy or benzylthio, refer to an arylor benzyl group attached to the molecule, or to another chain or ring,through an oxygen (“aryloxy”, benzyloxy e.g., —O-Ph, —OCH₂Ph) or sulfur(“arylthio” e.g., —S-Ph, —S—CH₂Ph) atom. Further, the terms“aryloxyalkyl”, “benzyloxyalkyl” “aryloxyalkenyl” and “aryloxyaliphatic”mean alkyl, alkenyl or aliphatic, as the case may be, substituted withone or more aryloxy or benzyloxy groups, as the case may be. In thiscase, the number of atoms for each aryl, aryloxy, alkyl, alkenyl oraliphatic will be indicated separately. Thus, a 5-6-memberedaryloxy(C₁₋₄alkyl) is a 5-6 membered aryl ring, attached via an oxygenatom to a C₁₋₄ alkyl chain which, in turn, is attached to the rest ofthe molecule via the terminal carbon of the C₁₋₄ alkyl chain.

As used herein, the terms “halogen” or “halo” mean F, Cl, Br, or I.

The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy”mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be,substituted with one or more halogen atoms. For example a C₁₋₃ haloalkylcould be —CFHCH₂CHF₂ and a C₁₋₂haloalkoxy could be —OC(Br)HCHF₂. Thisterm includes perfluorinated alkyl groups, such as —CF₃ and —CF₂CF₃.

As used herein, the term “cyano” refers to —CN or —C≡N.

The terms “cyanoalkyl”, “cyanoalkenyl”, “cyanoaliphatic”, and“cyanoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case maybe, substituted with one or more cyano groups. For example a C₁₋₃cyanoalkyl could be —C(CN)₂CH₂CH₃ and a C₁₋₂ cyanoalkenyl could be═CHC(CN)H₂.

As used herein, an “amino” group refers to —NH₂.

The terms “aminoalkyl”, “aminoalkenyl”, “aminoaliphatic”, and“aminoalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the case maybe, substituted with one or more amino groups. For example a C₁₋₃aminoalkyl could be —CH(NH₂)CH₂CH₂NH₂ and a C₁₋₂ aminoalkoxy could be—OCH₂CH₂NH₂.

The term “hydroxyl” or “hydroxy” refers to —OH.

The terms “hydroxyalkyl”, “hydroxyalkenyl”, “hydroxyaliphatic”, and“hydroxyalkoxy” mean alkyl, alkenyl, aliphatic or alkoxy, as the casemay be, substituted with one or more —OH groups. For example a C₁₋₃hydroxyalkyl could be —CH₂(CH₂OH)CH₃ and a C₄ hydroxyalkoxy could be—OCH₂C(CH₃)(OH)CH₃.

As used herein, a “carbonyl”, used alone or in connection with anothergroup refers to —C(O)— or —C(O)H. For example, as used herein, an“alkoxycarbonyl,” refers to a group such as —C(O)O(alkyl).

As used herein, an “oxo” refers to ═O, wherein oxo is usually, but notalways, attached to a carbon atom (e.g., it can also be attached to asulfur atom). An aliphatic chain can be optionally interrupted by acarbonyl group or can optionally be substituted by an oxo group, andboth expressions refer to the same: e.g. —CH₂—C(O)—CH₃.

As used herein, in the context of resin chemistry (e.g. using solidresins or soluble resins or beads), the term “linker” refers to abifunctional chemical moiety attaching a compound to a solid support orsoluble support.

In all other situations, a “linker”, as used herein, refers to adivalent group in which the two free valences are on different atoms(e.g. carbon or heteroatom) or are on the same atom but can besubstituted by two different substituents. For example, a methylenegroup can be C₁ alkyl linker (—CH₂—) which can be substituted by twodifferent groups, one for each of the free valences (e.g. as inPh-CH₂-Ph, wherein methylene acts as a linker between two phenyl rings).Ethylene can be C₂ alkyl linker (—CH₂CH₂—) wherein the two free valencesare on different atoms. The amide group, for example, can act as alinker when placed in an internal position of a chain (e.g. —CONH—). Alinker can be the result of interrupting an aliphatic chain by certainfunctional groups or of replacing methylene units on said chain by saidfunctional groups. E.g. a linker can be a C₁₋₆ aliphatic chain in whichup to two methylene units are substituted by —C(O)— or —NH— (as in—CH₂—NH—CH₂—C(O)—CH₂— or —CH₂—NH—C(O)—CH₂—). An alternative way todefine the same —CH₂—NH—CH₂—C(O)—CH₂— and —CH₂—NH—C(O)—CH₂— groups is asa C₃ alkyl chain optionally interrupted by up to two —C(O)— or —NH—moieties. Cyclic groups can also form linkers: e.g. a1,6-cyclohexanediyl can be a linker between two R groups, as in

A linker can additionally be optionally substituted in any portion orposition.

Divalent groups of the type R—CH═ or R₂C═, wherein both free valencesare in the same atom and are attached to the same substituent, are alsopossible. In this case, they will be referred to by their IUPAC acceptednames. For instance an alkylidene (such as, for example, a methylidene(═CH₂) or an ethylidene (═CH—CH₃)) would not be encompassed by thedefinition of a linker in this disclosure.

The term “protecting group”, as used herein, refers to an agent used totemporarily block one or more desired reactive sites in amultifunctional compound. In certain embodiments, a protecting group hasone or more, or preferably all, of the following characteristics: a)reacts selectively in good yield to give a protected substrate that isstable to the reactions occurring at one or more of the other reactivesites; and b) is selectively removable in good yield by reagents that donot attack the regenerated functional group. Exemplary protecting groupsare detailed in Greene, T. W. et al., “Protective Groups in OrganicSynthesis”, Third Edition, John Wiley & Sons, New York: 1999, the entirecontents of which is hereby incorporated by reference. The term“nitrogen protecting group”, as used herein, refers to an agents used totemporarily block one or more desired nitrogen reactive sites in amultifunctional compound. Preferred nitrogen protecting groups alsopossess the characteristics exemplified above, and certain exemplarynitrogen protecting groups are detailed in Chapter 7 in Greene, T. W.,Wuts, P. G in “Protective Groups in Organic Synthesis”, Third Edition,John Wiley & Sons, New York: 1999, the entire contents of which arehereby incorporated by reference.

As used herein, the term “displaceable moiety” or “leaving group” refersto a group that is associated with an aliphatic or aromatic group asdefined herein and is subject to being displaced by nucleophilic attackby a nucleophile.

As used herein, “amide coupling agent” or “amide coupling reagent” meansa compound that reacts with the hydroxyl moiety of a carboxy moietythereby rendering it susceptible to nucleophilic attack. Exemplary amidecoupling agents include DIC (diisopropylcarbodiimide), EDCI(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide), DCC(dicyclohexylcarbodiimide), BOP(benzotriazol-1-yloxy-tris(dimethylamino)-phosphoniumhexafluorophosphate), pyBOP((benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate),etc.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

Compound Embodiments

In a first aspect the invention relates to a compound according toFormula I′, or a pharmaceutically acceptable salt thereof,

wherein each of X¹ is selected from N, CH, C(C₁₋₄ alkyl), C(C₁₋₄haloalkyl), CCl and CF;X² is selected from N or C;W is either:i) absent, with J^(B) connected directly to the carbon atom bearing twoJ groups, each J is independently selected from hydrogen or methyl, n is1 and J^(B) is a C₁₋₇ alkyl chain optionally substituted by up to 9instances of fluorine; wherein, optionally, one —CH₂— unit of said C₁₋₇alkyl chain can be replaced by —O— or —S—.ii) a ring B that is a phenyl or a 5 or 6-membered heteroaryl ring,containing 1 or 2 ring heteroatoms selected from N, O or S; wherein withring B being the phenyl or 5 or 6-membered heteroaryl ring; each J ishydrogen; n is an integer selected from 0 to 3; and each J^(B) isindependently selected from halogen, —CN, a C₁₋₆ aliphatic, —OR^(B) or aC₃₋₈ cycloaliphatic group; wherein each said C₁₋₆ aliphatic and eachsaid C₃₋₈ cycloaliphatic group is optionally and independentlysubstituted with up to 3 instances of R³; each R^(B) is independentlyselected from hydrogen, a C₁₋₆ aliphatic or a C₃₋₈ cycloaliphatic;wherein each of said R^(B) that is a C₁₋₆ aliphatic and each of saidR^(B) that is a C₃₋₈ cycloaliphatic ring is optionally and independentlysubstituted with up to 3 instances of R^(3a);each R³ is independently selected from halogen, —CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄haloalkyl);each R^(3a) is independently selected from halogen, —CN, C₁₋₄ alkyl,C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄haloalkyl);o is an integer selected from 1 to 3;each J^(D) is independently selected from J^(A), halogen, —CN, —NO₂,—OR^(D), —SR^(D), —C(O)R^(D), —C(O)OR^(D), —OC(O)R^(D), —C(O)N(R^(D))₂,—N(R^(D))₂, —N(R^(d))C(O)R^(D), —N(R^(d))C(O)OR^(D),N(R^(d))C(O)N(R^(D))₂, —OC(O)N(R^(D))₂, —SO₂R^(D), —SO₂N(R^(D))₂,—N(R^(d))SO₂R^(D), a C₁₋₆ aliphatic, —(C₁₋₆ aliphatic)-R^(D), a C₃₋₈cycloaliphatic ring, a 6 to 10-membered aryl ring, a 4 to 8-memberedheterocyclic ring or a 5 to 10-membered heteroaryl ring; wherein eachsaid 4 to 8-membered heterocyclic ring and each said 5 to 10-memberedheteroaryl ring contains between 1 and 3 heteroatoms independentlyselected from O, N or S; and wherein each said C₁₋₆ aliphatic, each saidC₁₋₆ aliphatic portion of the —(C₁₋₆ aliphatic)-R^(D) moiety, each saidC₃₋₈ cycloaliphatic ring, each said 6 to 10-membered aryl ring, eachsaid 4 to 8-membered heterocyclic ring and each said 5 to 10-memberedheteroaryl ring is optionally and independently substituted with up to 5instances of R^(5d);J^(A) is selected from hydrogen, halogen, methyl, hydroxyl, methoxy,trifluoromethyl, trifluoromethoxy or —NR^(a)R^(b); wherein R^(a) andR^(b) are each independently selected from hydrogen, C₁₋₆ alkyl or a 3-6cycloalkyl ring; or wherein R^(a) and R^(b), together with the nitrogenatom to which they are both attached, form a 4-8 membered heterocyclicring, or a 5-membered heteroaryl ring optionally containing up to twoadditional heteroatoms selected from N, O and S; wherein each of said4-8 membered heterocyclic ring and 5-membered heteroaryl ring isoptionally and independently substituted by up to 6 instances offluorine;each R^(D) is independently selected from hydrogen, a C₁₋₆ aliphatic,—(C₁₋₆ aliphatic)-R^(f), a C₃₋₈ cycloaliphatic ring, a 4 to 10-memberedheterocyclic ring, phenyl or a 5 to 6-membered heteroaryl ring; whereineach said 4 to 10-membered heterocyclic ring and each said 5 to6-membered heteroaryl ring contains between 1 and 3 heteroatomsindependently selected from O, N or S; and wherein each said C₁₋₆aliphatic, each said C₁₋₆ aliphatic portion of the —(C₁₋₆aliphatic)-R^(f) moiety, each said C₃₋₈ cycloaliphatic ring, each said 4to 10-membered heterocyclic ring, each said phenyl and each said 5 to6-membered heteroaryl ring is optionally and independently substitutedwith up to 5 instances of R^(5a); wherein when any R^(D) is one of aC₁₋₆ aliphatic or a —(C₁₋₆ aliphatic)-R^(f) group, one or two —CH₂—units that form said C₁₋₆ aliphatic chains may, optionally, be replacedby a group independently selected from —N(R^(d))—, —CO— or —O—;each R^(d) is independently selected from hydrogen, a C₁₋₆ aliphatic,—(C₁₋₆ aliphatic)-R^(f), a C₃₋₈ cycloaliphatic ring, a 4 to 8-memberedheterocyclic ring, phenyl or a 5 to 6-membered heteroaryl ring; whereineach said 4 to 8-membered heterocyclic ring and each said 5 or6-membered heteroaryl ring contains between 1 and 3 heteroatomsindependently selected from 0, N or S; and wherein each said C₁₋₆aliphatic, each said C₁₋₆ aliphatic portion of the —(C₁₋₆aliphatic)-R^(f) moiety, each said C₃₋₈ cycloaliphatic ring, each said 4to 8-membered heterocyclic ring, each said phenyl and each said 5 to6-membered heteroaryl ring is optionally and independently substitutedby up to 5 instances of R^(5b); wherein when any R^(d) is one of a C₁₋₆aliphatic or a —(C₁₋₆ aliphatic)-R^(f) group, one or two —CH₂— unitsthat form said C₁₋₆ aliphatic chains may, optionally, be replaced by agroup independently selected from —N(R^(d))—, —CO— or —O—;each R^(f) is independently selected from a C₁₋₃ alkyl, a C₃₋₈cycloaliphatic ring, a 4 to 10-membered heterocyclic ring, phenyl or a 5to 6-membered heteroaryl ring; wherein each said 4 to 10-memberedheterocyclic ring and each said 5 to 6-membered heteroaryl ring containsbetween 1 and 4 heteroatoms independently selected from O, N or S; andwherein each said C₃₋₈ cycloaliphatic ring, each said 4 to 10-memberedheterocyclic ring, each said phenyl and each said 5 to 6-memberedheteroaryl ring is optionally and independently substituted by up to 5instances of R^(5c);when J^(D) is —C(O)N(R^(D))₂, —N(R^(D))₂, —N(R^(d))C(O)N(R^(D))₂,—OC(O)N(R^(D))₂ or —SO₂N(R^(D))₂, the two R^(D) groups together with thenitrogen atom attached to the two R^(D) groups may form a 4 to8-membered heterocyclic ring or a 5-membered heteroaryl ring; whereineach said 4 to 8-membered heterocyclic ring and each said 5-memberedheteroaryl ring optionally contains up to 3 additional heteroatomsindependently selected from N, O or S, in addition to the nitrogen atomto which the two R^(D) groups are attached; and wherein each said 4 to8-membered heterocyclic ring and each said 5-membered heteroaryl ring isoptionally and independently substituted by up to 5 instances of R⁵;when J^(D) is —N(R^(d))C(O)R^(D), the R^(D) group together with thecarbon atom attached to the R^(D) group, with the nitrogen atom attachedto the R^(d) group, and with the R^(d) group may form a 4 to 8-memberedheterocyclic ring or a 5-membered heteroaryl ring; wherein each said 4to 8-membered heterocyclic ring and each said 5-membered heteroaryl ringoptionally contains up to 2 additional heteroatoms independentlyselected from N, O or S, in addition to the nitrogen atom to which theR^(d) group is attached; and wherein each said 4 to 8-memberedheterocyclic ring and each said 5-membered heteroaryl ring is optionallyand independently substituted by up to 5 instances of R⁵;when J^(D) is —N(R^(d))C(O)OR^(D), the R^(D) group together with theoxygen atom attached to the R^(D) group, with the carbon atom of the—C(O)— portion of the —N(R^(d))C(O)OR^(D) group, with the nitrogen atomattached to the R^(d) group, and with said R^(d) group, may form a 4 to8-membered heterocyclic ring; wherein said 4 to 8-membered heterocyclicring optionally contains up to 2 additional heteroatoms independentlyselected from N, O or S, and is optionally and independently substitutedby up to 5 instances of R⁵;when J^(D) is —N(R^(d))C(O)N(R^(D))₂, one of the R^(D) groups attachedto the nitrogen atom, together with said nitrogen atom, and with the Natom attached to the R^(d) group and said R^(d) group may form a 4 to8-membered heterocyclic ring; wherein said 4 to 8-membered heterocyclicring optionally contains up to 2 additional heteroatoms independentlyselected from N, O or S, and is optionally and independently substitutedby up to 5 instances of R⁵;when J^(D) is —N(R^(d))SO₂R^(D), the R^(D) group together with thesulfur atom attached to the R^(D) group, with the nitrogen atom attachedto the R^(d) group, and with said R^(d) group may combine to form a 4 to8-membered heterocyclic ring; wherein said 4 to 8-membered heterocyclicring optionally contains up to 2 additional heteroatoms independentlyselected from N, O or S, and is optionally and independently substitutedby up to 5 instances of R⁵;each R⁵ is independently selected from halogen, —CN, C₁₋₆ alkyl, —(C₁₋₆alkyl)-R⁶, —OR⁶, —SR⁶, —COR⁶, —OC(O)R⁶, —C(O)OR⁶, —C(O)N(R⁶)₂,—C(O)N(R⁶)SO₂R⁶, —N(R⁶)C(O)R⁶, —N(R⁶)C(O)OR⁶, —N(R⁶)C(O)N(R⁶)₂, —N(R⁶)₂,—SO₂R⁶, —SO₂OH, —SO₂NHOH, —SO₂N(R⁶)₂, —SO₂N(R⁶)COOR⁶, —SO₂N(R⁶)C(O)R⁶,—N(R⁶)SO₂R⁶, —(C═O)NHOR⁶, a C₃₋₈ cycloalkyl ring, a 4 to 7-memberedheterocyclic ring, a 5 or 6-membered heteroaryl ring, phenyl, benzyl, anoxo group or a bicyclic group; wherein each of said 5 or 6-memberedheteroaryl ring or 4 to 7-membered heterocyclic ring contains up to 4ring heteroatoms independently selected from N, O and S; and whereineach of said C₁₋₆ alkyl, C₁₋₆ alkyl portion of the —(C₁₋₆ alkyl)-R⁶moiety, C₃₋₈ cycloalkyl ring, 4 to 7-membered heterocyclic ring, 5 or6-membered heteroaryl ring, benzyl or phenyl group is optionally andindependently substituted with up to 3 instances of halogen, C₁₋₄ alkyl,—OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —CONH₂,—COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo; whereinsaid bicyclic group contains ring one and ring two in a fused or bridgedrelationship, said ring one is a 4 to 7-membered heterocyclic ring, a 5or 6-membered heteroaryl ring, phenyl or benzyl, and said ring two is aphenyl ring or a 5 or 6-membered heteroaryl ring containing up to 3 ringheteroatoms selected from N, O or S; and wherein said bicyclic group isoptionally and independently substituted by up to six instances ofhalogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN,—COOH, —CONH₂, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) oroxo;two instances of R⁵, attached to the same or different atoms of J^(D),together with said atom or atoms to which they are attached, mayoptionally form a C₃₋₈ cycloalkyl ring, a 4 to 6-membered heterocyclicring; a phenyl or a 5 or 6-membered heteroaryl ring, resulting in abicyclic system wherein the two rings of the bicyclic system are in aspiro, fused or bridged relationship, wherein said 4 to 6-memberedheterocycle or said 5 or 6-membered heteroaryl ring contains up to fourring heteroatoms independently selected from N, O or S; and wherein saidC₃₋₈ cycloalkyl ring, 4 to 6-membered heterocyclic ring, phenyl or 5 or6-membered heteroaryl ring is optionally and independently substitutedby up to 3 instances of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, oxo, —C(O)O(C₁₋₄ alkyl), —C(O)OH, —NR(CO)O(C₁₋₄ alkyl),—CONH₂, —OH or halogen; wherein R is hydrogen or a C₁₋₂ alkyl;each R^(5a) and each R^(5b) is independently selected from halogen, —CN,C₁₋₆ alkyl, —(C₁₋₆ alkyl)R^(6a), —OR^(6a), —SR^(6a), —COR^(6a),—OC(O)R^(6a), —C(O)OR^(6a), —C(O)N(R^(6a))₂, —C(O)N(R^(6a))SO₂R^(6a),—N(R^(6a))C(O)R^(6a),—N(R^(6a))C(O)OR^(6a), —N(R^(6a))C(O)N(R^(6a))₂,—N(R^(6a))₂, —SO₂R^(6a), —SO₂OH, —SO₂NHOH, —SO₂N(R^(6a))₂,—SO₂N(R^(6a))COOR^(6a), —SO₂N(R^(6a))C(O)R^(6a), —N(R^(6a))SO₂R^(6a),—(C═O)NHOR^(6a), a C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclicring, a 5 or 6-membered heteroaryl ring, phenyl, benzyl, an oxo group ora bicyclic group; wherein each 5 or 6-membered heteroaryl ring or 4 to7-membered heterocyclic ring contains up to 4 ring heteroatomsindependently selected from N, O and S, wherein each of said C₁₋₆ alkyl,C₁₋₆ alkyl portion of the —(C₁₋₆ alkyl)R^(6a) moiety, C₃₋₈ cycloalkylring, 4 to 7-membered heterocyclic ring, 5 or 6-membered heteroarylring, benzyl or phenyl group is optionally and independently substitutedwith up to 3 instances of halogen, C₁₋₄ alkyl, C₁₋₄haloalkyl, —OH, —NH₂,—NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —CONH₂, —COO(C₁₋₄ alkyl),—O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo; wherein said bicyclic groupcontains ring one and ring two in a fused or bridged relationship, saidring one is a 4 to 7-membered heterocyclic ring, a 5 or 6-memberedheteroaryl ring, phenyl or benzyl, and said ring two is a phenyl ring ora 5 or 6-membered heteroaryl ring containing up to 3 ring heteroatomsselected from N, O or S; and wherein said bicyclic group is optionallyand independently substituted by up to six instances of halogen, C₁₋₄alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —CONH₂,—COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo;two instances of R^(5a) or two instances of R^(5b) attached to the sameor different atoms of R^(D) or R^(d), respectively, together with saidatom or atoms to which they are attached, may optionally form a C₃₋₈cycloalkyl ring, a 4 to 6-membered heterocyclic ring; a phenyl or a 5 or6-membered heteroaryl ring, resulting in a bicyclic system wherein thetwo rings of the bicyclic system are in a spiro, fused or bridgedrelationship with respect to each other; wherein said 4 to 6-memberedheterocycle or said 5 or 6-membered heteroaryl ring contains up to fourring heteroatoms independently selected from N, O or S; and wherein saidC₃₋₈ cycloalkyl ring, 4 to 6-membered heterocyclic ring, phenyl or 5 or6-membered heteroaryl ring is optionally and independently substitutedby up to 3 instances of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy,C₁₋₄haloalkoxy, oxo, —C(O)O(C₁₋₄ alkyl), —C(O)OH, —C(O)NH₂,—NR(CO)O(C₁₋₄ alkyl), —OH or halogen; wherein R is hydrogen or a C₁₋₂alkyl;each R^(5c) is independently selected from halogen, —CN, C₁₋₆ alkyl,—(C₁₋₆ alkyl)-R^(6b), —OR^(6b), —SR^(6b), —COR^(6b), —OC(O)R^(6b),—C(O)OR^(6b), —C(O)N(R^(6b))₂, —C(O)N(R^(6b))SO₂R^(6b),—N(R^(6b))C(O)R^(6b), —N(R^(6b))C(O)OR^(6b), —N(R^(6b))C(O)N(R^(6b))₂,—N(R^(6b))₂, —SO₂R^(6b), —SO₂OH, —SO₂NHOH, —SO₂N(R^(6b))₂,—SO₂N(R^(6b))COOR^(6b), —SO₂N(R^(6b))C(O)R^(6b), —N(R^(6b))SO₂R^(6b),—(C═O)NHOR^(6b), a C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclicring, a 5 or 6-membered heteroaryl ring, phenyl, benzyl, an oxo group,or a bicyclic group; wherein each of said 5 or 6-membered heteroarylring and each of said 4 to 7-membered heterocyclic ring contains up to 4ring heteroatoms independently selected from N, O and S; and whereineach of said C₁₋₆ alkyl, C₁₋₆ alkyl portion of said —(C₁₋₆ alkyl)-R^(6b)moiety, each of said C₃₋₈ cycloalkyl ring, each of said 4 to 7-memberedheterocyclic ring, each of said 5 or 6-membered heteroaryl ring, each ofsaid benzyl and each of said phenyl group is optionally andindependently substituted with up to 3 instances of halogen, C₁₋₄ alkyl,—OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —CONH₂,—COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo; whereinsaid bicyclic group contains a first ring and a second ring in a fusedor bridged relationship, said first ring is a 4 to 7-memberedheterocyclic ring, a 5 or 6-membered heteroaryl ring, phenyl or benzyl,and said second ring is a phenyl ring or a 5 or 6-membered heteroarylring containing up to 3 ring heteroatoms selected from N, O or S; andwherein said bicyclic group is optionally and independently substitutedby up to six instances of halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —CONH₂, —COO(C₁₋₄ alkyl), —O(C₁₋₄alkyl), —O(C₁₋₄ haloalkyl) or oxo;two instances of R^(5c) attached to the same or different atoms ofR^(f), together with said atom or atoms to which it is attached, mayoptionally form a C₃₋₈ cycloalkyl ring, a 4 to 6-membered heterocyclicring; a phenyl or a 5 or 6-membered heteroaryl ring, resulting in abicyclic system wherein the two rings of the bicyclic system are in aspiro, fused or bridged relationship with respect to each other; whereinsaid 4 to 6-membered heterocycle or said 5 or 6-membered heteroaryl ringcontains up to four ring heteroatoms independently selected from N, O orS; and wherein said C₃₋₈ cycloalkyl ring, 4 to 6-membered heterocyclicring, phenyl or 5 or 6-membered heteroaryl ring is optionally andindependently substituted by up to 3 instances of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, oxo, —C(O)O(C₁₋₄ alkyl),—C(O)OH, —CONH₂, —NR(CO)O(C₁₋₄ alkyl), —OH or halogen; wherein R ishydrogen or a C₁₋₂ alkyl;each R^(5d) is independently selected from halogen, —CN, C₁₋₆ alkyl,—(C₁₋₆ alkyl)-R⁶, —OR⁶, —SR⁶, —COR⁶, —OC(O)R⁶, —C(O)OR⁶, —C(O)N(R⁶)₂,—N(R⁶)C(O)R⁶, —N(R⁶)C(O)OR⁶, —N(R⁶)C(O)N(R⁶)₂, —N(R⁶)₂, —SO₂R⁶, —SO₂OH,—SO₂NHOH, —SO₂N(R⁶)COR⁶, —SO₂N(R⁶)₂, —N(R⁶)SO₂R⁶, a C₇₋₁₂ aralkyl, aC₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclic ring, a 5 or6-membered heteroaryl ring, phenyl or an oxo group; wherein each 5 or6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring containsup to four ring heteroatoms independently selected from N, O and S,wherein each of said C₁₋₆ alkyl, C₁₋₆ alkyl portion of the —(C₁₋₆alkyl)-R⁶ moiety, C₇₋₁₂ aralkyl, C₃₋₈ cycloalkyl ring, 4 to 7-memberedheterocyclic ring, 5 or 6-membered heteroaryl ring or phenyl group isoptionally and independently substituted with up to 3 instances ofhalogen, C₁₋₄ alkyl, C₁₋₄ (haloalkyl), —OH, —NH₂, —NH(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)₂, —CN, —COOH, —CONH₂, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl),—O(C₁₋₄ haloalkyl) or oxo; two instances of R^(5d) attached to the sameor different atoms of J^(D), together with said atom or atoms of J^(D)to which they are attached, may optionally form a C₃₋₈ cycloalkyl ring,a 4 to 6-membered heterocyclic ring; a phenyl or a 5 or 6-memberedheteroaryl ring, resulting in a bicyclic system wherein the two rings ofthe bicyclic system are in a spiro, fused or bridged relationship withrespect to each other; wherein said 4 to 6-membered heterocycle or said5 or 6-membered heteroaryl ring contains up to four ring heteroatomsindependently selected from N, O or S; and wherein said C₃₋₈ cycloalkylring, 4 to 6-membered heterocyclic ring, phenyl or 5 or 6-memberedheteroaryl ring is optionally and independently substituted by up to 3instances of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,oxo, —C(O)O(C₁₋₄ alkyl), —C(O)OH, —NR(CO)O(C₁₋₄ alkyl), —C(O)NH₂, —OH orhalogen; wherein R is hydrogen or a C₁₋₂ alkyl;each R⁶ is independently selected from hydrogen, a C₁₋₆ alkyl, phenyl,benzyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclic ring or a5 or 6-membered heteroaryl ring, wherein each of said C₁₋₆ alkyl, eachof said phenyl, each of said benzyl, each of said C₃₋₈ cycloalkyl group,each of said 4 to 7-membered heterocyclic ring and each of said 5 or6-membered heteroaryl ring is optionally and independently substitutedwith up to 3 instances of halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —C(O)NH₂, —COO(C₁₋₄ alkyl), —O(C₁₋₄alkyl), —O(C₁₋₄ haloalkyl) or oxo, wherein each of said 5 or 6-memberedheteroaryl ring or 4 to 7-membered heterocyclic ring contains up to 4ring heteroatoms independently selected from N, O and S;each R^(6a) is independently selected from hydrogen, a C₁₋₆ alkyl,phenyl, benzyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclicring or a 5 or 6-membered heteroaryl ring, wherein each of said C₁₋₆alkyl, each of said phenyl, each of said benzyl, each of said C₃₋₈cycloalkyl group, each of said 4 to 7-membered heterocyclic ring andeach of said 5 or 6-membered heteroaryl ring is optionally andindependently substituted with up to 3 instances of halogen, C₁₋₄ alkyl,—OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —C(O)NH₂,—COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo, whereineach of said 5 or 6-membered heteroaryl ring or 4 to 7-memberedheterocyclic ring contains up to 4 ring heteroatoms independentlyselected from N, O and S;each R^(6b) is independently selected from hydrogen, a C₁₋₆ alkyl,phenyl, benzyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclicring or a 5 or 6-membered heteroaryl ring, wherein each of said C₁₋₆alkyl, each of said phenyl, each of said benzyl, each of said C₃₋₈cycloalkyl group, each of said 4 to 7-membered heterocyclic ring andeach of said 5 or 6-membered heteroaryl ring is optionally andindependently substituted with up to 3 instances of halogen, C₁₋₄ alkyl,—OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —C(O)NH₂,—C(O)N(C₁₋₆ alkyl)₂, —C(O)NH(C₁₋₆ alkyl), —C(O)N(C₁₋₆ haloalkyl)₂,—C(O)NH(C₁₋₆ haloalkyl), C(O)N(C₁₋₆ alkyl)(C₁₋₆ haloalkyl), —COO(C₁₋₆alkyl), —COO(C₁₋₆ haloalkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo,wherein each of said 5 or 6-membered heteroaryl ring or 4 to 7-memberedheterocyclic ring contains up to 4 ring heteroatoms independentlyselected from N, O and S; whereintwo instances of R⁶ linked to the same nitrogen atom of R⁵ or R^(5d),together with said nitrogen atom of R⁵ or R^(5d), respectively, may forma 5 to 8-membered heterocyclic ring or a 5-membered heteroaryl ring;wherein each said 5 to 8-membered heterocyclic ring and each said5-membered heteroaryl ring optionally contains up to 2 additionalheteroatoms independently selected from N, O or S;two instances of R^(6a) linked to a nitrogen atom of R^(5a) or R^(5b),together with said nitrogen, may form a 5 to 8-membered heterocyclicring or a 5-membered heteroaryl ring; wherein each said 5 to 8-memberedheterocyclic ring and each said 5-membered heteroaryl ring optionallycontains up to 2 additional heteroatoms independently selected from N, Oor S;two instances of R^(6b) linked to a nitrogen atom of R^(5c), togetherwith said nitrogen, may form a 5 to 8-membered heterocyclic ring or a5-membered heteroaryl ring; wherein each said 5 to 8-memberedheterocyclic ring and each said 5-membered heteroaryl ring optionallycontains up to 2 additional heteroatoms independently selected from N, Oor S;two J^(D) groups attached to two vicinal ring D atoms, taken togetherwith said two vicinal ring D atoms, may form a 5 to 7-memberedheterocycle or a 5-membered heteroaryl ring that is fused to ring D;wherein said 5 to 7-membered heterocycle or said 5-membered ringheteroaryl contains from 1 to 3 heteroatoms independently selected fromN, O or S; and wherein said 5 to 7-membered heterocycle or said5-membered heteroaryl ring is optionally and independently substitutedby up to 3 instances of oxo or —(Y)—R⁹;wherein Y is either absent or is a linkage in the form of a C₁₋₆ alkylchain, optionally substituted by up to 6 instances of fluoro; andwherein when Y is said C₁₋₆ alkyl chain, up to 3 methylene units of thisalkyl chain, can be replaced by a group selected from —O—, —C(O)— or—N((Y)—R⁹⁰)—, wherein

-   -   i) when Y is absent, each R⁹⁰ is independently selected from        hydrogen, —COR¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂, —C(O)N(R¹⁰)SO₂R¹⁰,        —SO₂R¹⁰, —SO₂N(R¹⁰)₂, —SO₂N(R¹⁰)COOR¹⁰, —SO₂N(R¹⁰)C(O)R¹⁰,        —(C═O)NHOR¹⁰, C₃₋₆ cycloalkyl ring, a 4-8-membered heterocyclic        ring, a phenyl ring or a 5-6 membered heteroaroaryl ring;        wherein each said 4 to 8-membered heterocyclic ring or 5 to        6-membered heteroaryl ring contains up to 4 ring heteroatoms        independently selected from N, O or S; and wherein each of said        C₃₋₆ cycloalkyl rings, each of said 4 to 8-membered heterocyclic        rings, each of said phenyl and each of said 5 to 6-membered        heteroaryl rings is optionally and independently substituted        with up to 3 instances of R¹¹; and    -   ii) when Y is present, each R⁹⁰ is independently selected from        hydrogen, halogen, —CN, —OR¹⁰, —COR¹⁰, —OC(O)R¹⁰, —C(O)OR¹⁰,        —C(O)N(R¹⁰)₂, —C(O)N(R¹⁰)SO₂R¹⁰, —N(R¹⁰)C(O)R¹⁰,        —N(R¹⁰)C(O)OR¹⁰, —N(R¹⁰)C(O)N(R¹⁰)₂, —N(R¹⁰)₂, —SO₂R¹⁰,        —SO₂N(R¹⁰)₂, —SO₂N(R¹⁰)COOR¹⁰, —SO₂N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)SO₂R¹⁰,        —(C═O)NHOR¹⁰, C₃₋₆ cycloalkyl ring, a 4-8-membered heterocyclic        ring, a phenyl ring or a 5-6 membered heteroaroaryl ring;        wherein each said 4 to 8-membered heterocyclic ring or 5 to        6-membered heteroaryl ring contains up to 4 ring heteroatoms        independently selected from N, O or S; and wherein each of said        C₃₋₆ cycloalkyl rings, each of said 4 to 8-membered heterocyclic        rings, each of said phenyl and each of said 5 to 6-membered        heteroaryl rings is optionally and independently substituted        with up to 3 instances of R¹¹;        each R⁹ is independently selected from hydrogen, halogen, —CN,        —OR¹⁰, —COR¹⁰, —OC(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂,        —C(O)N(R¹⁰)SO₂R¹⁰, —N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)C(O)OR¹⁰,        —N(R¹⁰)C(O)N(R¹⁰)₂, —N(R¹⁰)₂, —SO₂R¹⁰, —SO₂N(R¹⁰)₂,        —SO₂N(R¹⁰)COOR¹⁰, —SO₂N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)SO₂R¹⁰,        —(C═O)NHOR¹⁰, C₃₋₆ cycloalkyl ring, a 4-8-membered heterocyclic        ring, a phenyl ring or a 5-6 membered heteroaryl ring; wherein        each said 4 to 8-membered heterocyclic ring or 5 to 6-membered        heteroaryl ring contains up to 4 ring heteroatoms independently        selected from N, O or S; and wherein each of said C₃₋₆        cycloalkyl rings, each of said 4 to 8-membered heterocyclic        rings, each of said phenyl and each of said 5 to 6-membered        heteroaryl rings is optionally and independently substituted        with up to 3 instances of R¹¹;        each R¹⁰ is independently selected from hydrogen, a C₁₋₆ alkyl,        —(C₁₋₆ alkyl)-R¹³, phenyl, benzyl, a C₃₋₈ cycloalkyl ring, a 4        to 7-membered heterocyclic ring or a 5 or 6-membered heteroaryl        ring, wherein each 5 or 6-membered heteroaryl ring or 4 to        7-membered heterocyclic ring contains up to 4 ring heteroatoms        independently selected from N, O and S; and wherein each of said        C₁₋₆ alkyl, C₁₋₆ alkyl portion of said —(C₁₋₆ alkyl)-R¹³ moiety,        each said phenyl, each said benzyl, each said C₃₋₈ cycloalkyl        group, each said 4 to 7-membered heterocyclic ring and each 5 or        6-membered heteroaryl ring is optionally and independently        substituted with up to 3 instances of R^(11a);        each R¹³ is independently selected from a phenyl, a benzyl, a        C₃₋₆ cycloalkyl ring, a 4 to 7-membered heterocyclic ring or a 5        or 6-membered heteroaryl ring, wherein each 5 or 6-membered        heteroaryl ring or 4 to 7-membered heterocyclic ring contains up        to 4 ring heteroatoms independently selected from N, O and S;        and wherein each said phenyl, each of said benzyl, each said        C₃₋₈ cycloalkyl group, each said 4 to 7-membered heterocyclic        ring and each 5 or 6-membered heteroaryl ring is optionally and        independently substituted with up to 3 instances of R^(11b);        each R¹¹ is independently selected from halogen, oxo, C₁₋₆        alkyl, —CN, —OR¹², —COR¹², —C(O)OR¹², —C(O)N(R¹²)₂,        —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)₂, —N(R¹²)₂,        —SO₂R¹², —SO₂N(R¹²)₂ or —N(R¹²)SO₂R¹²; wherein each of said C₁₋₆        alkyl is optionally and independently substituted by up to 6        instances of fluoro and/or 3 instances of R¹²;        each R^(11a) is independently selected from halogen, oxo, C₁₋₆        alkyl, —CN, —OR¹², —COR¹², —C(O)OR¹², —C(O)N(R¹²)₂,        —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)₂, —N(R¹²)₂,        —SO₂R¹², —SO₂N(R¹²)₂ or —N(R¹²)SO₂R¹²; wherein each of said C₁₋₆        alkyl is optionally and independently substituted by up to 6        instances of fluoro and/or 3 instances of R¹²; and        each R^(11b) is independently selected from halogen, C₁₋₆ alkyl,        oxo, —CN, —OR¹², —COR¹², —C(O)OR¹², —C(O)N(R¹²)₂,        —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹², —N(R¹²)C(O)N(R¹²)₂, —N(R¹²)₂,        —SO₂R¹², —SO₂N(R¹²)₂ or —N(R¹²)SO₂R¹²; wherein each of said C₁₋₆        alkyl is optionally and independently substituted by up to 6        instances of fluoro and/or 3 instances of R¹²;        each R¹² is selected from hydrogen, a C₁₋₆ alkyl, phenyl,        benzyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclic        ring or a 5 or 6-membered heteroaryl ring, wherein each 5 or        6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring        contains up to 4 ring heteroatoms independently selected from N,        O and S; and wherein each of said C₁₋₆ alkyl, each said phenyl,        each said benzyl, each said C₃₋₈ cycloalkyl group, each said 4        to 7-membered heterocyclic ring and each 5 or 6-membered        heteroaryl ring is optionally and independently substituted with        up to 3 instances of halogen, C₁₋₄ alkyl, C₁₋₄ (fluoroalkyl),        —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —CONH₂,        —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ fluoroalkyl) or oxo.        R^(C) is either        i) a ring C; or        ii) is selected from halogen, —CN, C₁₋₆ alkyl, —(C₁₋₆        alkyl)-R^(N), —COR⁷, —C(O)OR⁷, —C(O)N(R⁷)₂, —N(R⁷)C(O)R⁷,        —N(R⁷)C(O)OR⁷, —N(R⁷)C(O)N(R⁷)₂, —N(R⁷)₂, —SO₂R⁷, —SO₂N(R⁷)₂,        —C(O)N(R⁷)SO₂R⁷, —SO₂N(R⁷)COOR⁷, —SO₂N(R⁷)C(O)R⁷, or —N(R⁷)SO₂R⁷        or —(C═O)NHOR⁷; wherein each said C₁₋₆ alkyl, each C₁₋₆ alkyl        portion of said —(C₁₋₆ alkyl)-R^(N), is optionally and        independently substituted with up to 6 instances of fluoro and        up to 2 instances of —CN, —OR⁸, oxo, —N(R⁸)₂, —N(R⁸)C(O)R⁸,        —N(R⁸)C(O)OR⁸, —N(R⁸)C(O)N(R⁸)₂, —SO₂R⁸, —SO₂N(R⁸)₂, —NHOR⁸,        —SO₂N(R⁸)COOR⁸, —SO₂N(R⁸)C(O)R⁸, —N(R⁸)SO₂R⁸;        wherein each R⁷ is independently selected from hydrogen, C₁₋₆        alkyl, C₁₋₆ fluoroalkyl, a C₃₋₈ cycloalkyl ring, phenyl, a 4 to        7-membered heterocyclic ring or a 5 or 6-membered heteroaryl        ring; wherein each of said 5 or 6-membered heteroaryl ring or 4        to 7-membered heterocyclic ring contains up to 4 ring        heteroatoms independently selected from N, O and S; and wherein        each of said C₁₋₆ alkyl, each of said phenyl, each of said C₃₋₈        cycloalkyl group, each of said 4 to 7-membered heterocyclic ring        and each of said 5 or 6-membered heteroaryl ring is optionally        and independently substituted with up to 3 instances of halogen,        C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN,        —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or        oxo;        each R⁸ is independently selected from hydrogen, C₁₋₆ alkyl,        C₁₋₆ fluoroalkyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered        heterocyclic ring or a 5 or 6-membered heteroaryl ring; wherein        each of said 5 or 6-membered heteroaryl ring or 4 to 7-membered        heterocyclic ring contains up to 4 ring heteroatoms        independently selected from N, O and S; and wherein each of said        C₁₋₆ alkyl, each of said phenyl, each of said C₃₋₈ cycloalkyl        group, each of said 4 to 7-membered heterocyclic ring and each        of said 5 or 6-membered heteroaryl ring is optionally and        independently substituted with up to 3 instances of halogen,        C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN,        —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or        oxo;        each R^(N) is independently selected from a phenyl ring, a        monocyclic 5 or 6-membered heteroaryl ring, a monocyclic C₃₋₆        cycloaliphatic ring, or a monocyclic 4 to 6-membered        heterocycle; wherein said monocyclic 5 or 6-membered heteroaryl        ring or said monocyclic 4 to 6-membered heterocycle contain        between 1 and 4 heteroatoms selected from N, O or S; wherein        said monocyclic 5 or 6-membered heteroaryl ring is not a        1,3,5-triazinyl ring; and wherein said phenyl, said monocyclic 5        to 6-membered heteroaryl ring, said monocyclic C₃₋₆        cycloaliphatic ring, or said monocyclic 4 to 6-membered        heterocycle is optionally and independently substituted with up        to 6 instances of fluoro and/or up to 3 instances of J^(M);        each J^(M) is independently selected from —CN, a C₁₋₆ aliphatic,        —OR^(M), —SR^(M), —N(R^(M))₂, a C₃₋₈ cycloaliphatic ring or a 4        to 8-membered heterocyclic ring; wherein said 4 to 8-membered        heterocyclic ring contains 1 or 2 heteroatoms independently        selected from N, O or S; wherein each said C₁₋₆ aliphatic, each        said C₃₋₈ cycloaliphatic ring and each said 4 to 8-membered        heterocyclic ring, is optionally and independently substituted        with up to 3 instances of R^(7c);        each R^(M) is independently selected from hydrogen, a C₁₋₆        aliphatic, a C₃₋₈ cycloaliphatic ring or a 4 to 8-membered        heterocyclic ring; wherein each said 4 to 8-membered        heterocyclic ring contains between 1 and 3 heteroatoms        independently selected from O, N or S; and wherein        ring C is a phenyl ring, a monocyclic 5 or 6-membered heteroaryl        ring, a bicyclic 8 to 10-membered heteroaryl ring, a monocyclic        3 to 10-membered cycloaliphatic ring, or a monocyclic 4 to        10-membered heterocycle; wherein said monocyclic 5 or 6-membered        heteroaryl ring, said bicyclic 8 to 10-membered heteroaryl ring,        or said monocyclic 4 to 10-membered heterocycle contain between        1 and 4 heteroatoms selected from N, O or S; wherein said        monocyclic 5 or 6-membered heteroaryl ring is not a        1,3,5-triazinyl ring; and wherein said phenyl, monocyclic 5 to        6-membered heteroaryl ring, bicyclic 8 to 10-membered heteroaryl        ring, monocyclic 3 to 10-membered cycloaliphatic ring, or        monocyclic 4 to 10-membered heterocycle is optionally and        independently substituted with up to p instances of J^(C)′;        wherein p is 0 or an integer selected from 1 to 3;        each J^(C)′ is independently selected from halogen, —CN, —NO₂, a        C₁₋₆ aliphatic, —OR^(H), —SR^(H), —N(R^(H))₂, a C₃₋₈        cycloaliphatic ring or a 4 to 8-membered heterocyclic ring;        wherein said 4 to 8-membered heterocyclic ring contains 1 or 2        heteroatoms independently selected from N, O or S; wherein each        said C₁₋₆ aliphatic, each said C₃₋₈ cycloaliphatic ring and each        said 4 to 8-membered heterocyclic ring, is optionally and        independently substituted with up to 3 instances of R^(7d); or        alternatively, two J^(C)′ groups attached to two vicinal ring C        atoms, taken together with said two vicinal ring C atoms, form a        5 to 7-membered heterocycle that is a new ring fused to ring C;        wherein said 5 to 7-membered heterocycle contains from 1 to 2        heteroatoms independently selected from N, O or S;        each R^(H) is independently selected from hydrogen, a C₁₋₆        aliphatic, a C₃₋₈ cycloaliphatic ring or a 4 to 8-membered        heterocyclic ring; wherein each said 4 to 8-membered        heterocyclic ring contains between 1 and 3 heteroatoms        independently selected from O, N or S; alternatively, two        instances of R^(H) linked to the same nitrogen atom of        —N(R^(H))₂, together with said nitrogen atom of —N(R^(H))₂, form        a 4 to 8-membered heterocyclic ring or a 5-membered heteroaryl        ring; wherein each said 4 to 8-membered heterocyclic ring and        each said 5-membered heteroaryl ring optionally contains up to 2        additional heteroatoms independently selected from N, O or S;        each R^(7c) is independently selected from hydrogen, halogen,        —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl ring,        —OR^(8b), —SR^(8b), —N(R^(8b))₂, —C(O)O(C₁₋₄ alkyl), —C(O)OH,        —NR(CO)CO(C₁₋₄ alkyl) or an oxo group; wherein each said        cycloalkyl group is optionally and independently substituted        with up to 3 instances of halogen;        each R^(7d) is independently selected from hydrogen, halogen,        —CN, —NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl ring,        —OR⁸c, —SR^(8c), —N(R^(8c))₂, or an oxo group; wherein each said        cycloalkyl group is optionally and independently substituted        with up to 3 instances of halogen;        each R^(8b) is independently selected from hydrogen, C₁₋₆ alkyl,        C₁₋₆ fluoroalkyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered        heterocyclic ring or a 5 or 6-membered heteroaryl ring; wherein        each of said 5 or 6-membered heteroaryl ring or 4 to 7-membered        heterocyclic ring contains up to 4 ring heteroatoms        independently selected from N, O and S; and wherein each of said        C₁₋₆ alkyl, each of said phenyl, each of said C₃₋₈ cycloalkyl        group, each of said 4 to 7-membered heterocyclic ring and each        of said 5 or 6-membered heteroaryl ring is optionally and        independently substituted with up to 3 instances of halogen,        C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN,        —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or        oxo;        each R^(8c) is independently selected from hydrogen, C₁₋₆ alkyl,        C₁₋₆ fluoroalkyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered        heterocyclic ring or a 5 or 6-membered heteroaryl ring; wherein        each of said 5 or 6-membered heteroaryl ring or 4 to 7-membered        heterocyclic ring contains up to 4 ring heteroatoms        independently selected from N, O and S; and wherein each of said        C₁₋₆ alkyl, each of said phenyl, each of said C₃₋₈ cycloalkyl        group, each of said 4 to 7-membered heterocyclic ring and each        of said 5 or 6-membered heteroaryl ring is optionally and        independently substituted with up to 3 instances of halogen,        C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN,        —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or        oxo;        provided that the compound is not a compound depicted below:

wherein J^(D) is either an ethylene or —N(Me)₂; J^(A) is either hydrogenor methyl and J^(B) is either fluoro or C₁₋₂ alkoxy.

In some embodiments of the compounds of Formula I′, W is absent. In someof these embodiments, wherein W is absent, the compound is representedby Formula II′a:

wherein Q represents a C₁₋₇ alkyl group, optionally substituted with upto 9 instances of fluorine. In other embodiments Q is substituted withup to 5 instances of fluorine.

In still other embodiments of Formula I′ wherein W is absent, thecompound is represented by Formula III′a:

wherein,Q′ is a C₁₋₅ alkyl chain, optionally substituted by up to 6 instances offluorine. In some of these embodiments, X² is N, and the moiety—N(R¹)(R²) is absent. In other embodiments, X² is C, and the moiety—N(R¹)(R²) is present. In some of these embodiments:R¹ and R², together with the nitrogen atom to which they are attached,form a 4 to 8-membered heterocyclic ring or 5-membered heteroaryl ring;wherein said 4 to 8-membered heterocyclic ring or 5-membered heteroarylring optionally contains, in addition to the nitrogen atom to which R¹and R² are attached, up to 3 ring heteroatoms independently selectedfrom N, O or S, and is optionally substituted by up to 5 instances ofR^(5e);each R^(5e) is independently selected from halogen, —CN, C₁₋₆ alkyl,—(C₁₋₄ alkyl)-R⁶, a C₃₋₈ cycloalkyl ring, C₁₋₄ cyanoalkyl, —OR⁶, —SR⁶,—OCOR⁶, —COR⁶, —C(O)OR⁶, —C(O)N(R⁶)₂, —N(R⁶)C(O)R⁶, —N(R⁶)₂, —SO₂R⁶,—SO₂OH, —SO₂NHOH, —SO₂N(R⁶)COR⁶, —SO₂N(R⁶)₂, —N(R⁶)SO₂R⁶, benzyl, phenylor an oxo group; wherein each said phenyl ring and each said benzylgroup, is optionally and independently substituted with up to 3instances of halogen, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN,C₁₋₄ alkyl, C₁₋₄haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl); andwherein each said C₁₋₆ alkyl, each C₁₋₄ alkyl portion of said —(C₁₋₄alkyl)-R⁶ moiety, and each said C₃₋₈ cycloalkyl ring is optionally andindependently substituted with up to 3 instances of halogen; whereineach R⁶ is independently selected from hydrogen, a C₁₋₆ alkyl, a C₂₋₄alkenyl, phenyl, benzyl, or a C₃₋₈ cycloalkyl ring; wherein each saidC₁₋₆ alkyl, each said C₂₋₄ alkenyl, each said phenyl, each said benzyland each said C₃₋₈ cycloalkyl group is optionally and independentlysubstituted with up to 3 instances of halogen;two of the instances of R^(5e) attached to the same or different atomsof said ring formed by R¹, R² and the nitrogen to which R¹ and R² areattached, together with said atom or atoms, may optionally form a C₃₋₈cycloalkyl ring, a 4 to 6-membered heterocyclic ring; a phenyl or a 5 or6-membered heteroaryl ring, resulting in a bicyclic system wherein thetwo rings of the bicyclic system are in a spiro, fused or bridgedrelationship, wherein said 4 to 6-membered heterocycle or said 5 or6-membered heteroaryl ring contains up to three ring heteroatomsindependently selected from N, O or S; and wherein said C₃₋₈ cycloalkylring, 4 to 6-membered heterocyclic ring, phenyl or 5 or 6-memberedheteroaryl ring is optionally and independently substituted by up to 3instances of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, C₁₋₄ haloalkoxy,oxo, —C(O)O(C₁₋₄ alkyl), —C(O)OH, —C(O)NH₂, —NR(CO)O(C₁₋₄ alkyl), —OH orhalogen; wherein R is hydrogen or a C₁₋₂ alkyl.

In some of these embodiments, alternatively, R¹ and R² are eachindependently selected from hydrogen, C₁₋₆ alkyl, a C₃₋₈ cycloalkylring, a 4 to 8-membered heterocyclic ring, a 5 or 6-membered heteroaryl,phenyl or a C₁₋₆ alkyl-R^(Y); wherein each of said 4 to 8-memberedheterocyclic ring and each of said 5 or 6-membered heteroaryl ringcontains up to 3 ring heteroatoms independently selected from N, O andS; and wherein each of said C₁₋₆ alkyl, C₁₋₆ alkyl portion of each saidC₁₋₆ alkyl-R^(Y) moiety, C₃₋₈ cycloalkyl ring, 4 to 8-memberedheterocyclic ring group, 5 or 6-membered heteroaryl, phenyl and C₁₋₆alkyl-R^(Y) is optionally and independently substituted with up to 5instances of R^(5f);

R^(Y) is selected from a C₃₋₈ cycloalkyl ring, a 4 to 8-memberedheterocyclic ring, phenyl, or a 5 to 6-membered heteroaryl ring; whereineach of said 4 to 8-membered heterocyclic ring or 5 to 6-memberedheteroaromatic ring contains between 1 and 4 ring heteroatomsindependently selected from N, O or S; and wherein each of said C₃₋₈cycloalkyl ring, each of said 4 to 8-membered heterocyclic ring, each ofsaid phenyl, and each of said 5 to 6-membered heteroaryl ring isoptionally substituted with up to 5 instances of R^(5g);each R⁵ is independently selected from halogen, —CN, C₁₋₆ alkyl, —(C₁₋₄alkyl)-R^(6a), a C₇₋₁₂ aralkyl, C₃₋₈ cycloalkyl ring, C₁₋₄ cyanoalkyl,—OR^(6a), —SR^(6a), —OCOR^(6a), —COR^(6a), —C(O)OR^(6a),—C(O)N(R^(6a))₂, —N(R^(6a))C(O)R^(6a), —N(R^(6a))₂, —SO₂R^(6a),—SO₂N(R^(6a))₂, —N(R^(6a))SO₂R^(6a), —SO₂OH, —SO₂NHOH,—SO₂N(R^(6a))COR^(6a), phenyl or an oxo group; wherein each said phenylgroup is optionally and independently substituted with up to 3 instancesof halogen, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —NO₂, —CN, C₁₋₄alkyl, C₁₋₄ haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄ haloalkyl); and whereineach said C₇₋₁₂ aralkyl, C₁₋₆ alkyl, C₁₋₄ alkyl portion of each said—(C₁₋₄ alkyl)-R^(6a) and each said C₃₋₈ cycloalkyl group is optionallyand independently substituted with up to three instances of halogen;each R^(6a) is independently selected from hydrogen, a C₁₋₆ alkyl, aC₂₋₄ alkenyl, phenyl, benzyl, or a C₃₋₈ cycloalkyl ring; wherein eachsaid C₁₋₆ alkyl, each said C₂₋₄ alkenyl, each said phenyl, each saidbenzyl and each said C₃₋₈ cycloalkyl group is optionally andindependently substituted with up to 3 instances of halogen;each R^(5g) is independently selected from halogen, —CN, C₁₋₆ alkyl,—(C₁₋₄ alkyl)-R^(6b), a benzyl, C₃₋₈ cycloalkyl ring, C₁₋₄ cyanoalkyl,—OR^(6b), —SR^(6b), —OCOR^(6b), —COR^(6b), —C(O)OR^(6b),—C(O)N(R^(6b))₂, —N(R^(6b))C(O)R^(6b), —N(R^(6b))₂, —SO₂R^(6b),—SO₂N(R^(6b))₂, —N(R^(6b))SO₂R^(6b), —SO₂OH, —SO₂NHOH,—SO₂N(R^(6b))COR^(6b), phenyl or an oxo group; wherein each said phenyland each said benzyl group is optionally and independently substitutedwith up to 3 instances of halogen, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)₂, —NO₂, —CN, C₁₋₄ alkyl, C₁₋₄haloalkyl, —O(C₁₋₄ alkyl) or —O(C₁₋₄haloalkyl); and wherein each said C₁₋₆ alkyl, C₁₋₄ alkyl portion of eachsaid (C₁₋₄ alkyl)-R^(6b) moiety and each said C₃₋₈ cycloalkyl group isoptionally and independently substituted with up to 3 instances ofhalogen;each R^(6b) is independently selected from hydrogen, a C₁₋₆ alkyl, aC₂₋₄ alkenyl, phenyl, benzyl, or a C₃₋₈ cycloalkyl ring; wherein eachsaid C₁₋₆ alkyl, each said C₂₋₄ alkenyl, each said phenyl, each saidbenzyl and each said C₃₋₈ cycloalkyl group is optionally andindependently substituted with up to 3 instances of halogen.

In some embodiments, alternatively, two instances of R^(5g) attached tothe same or different ring atoms of R^(Y), together with said ring atomor atoms, form a C₃₋₈ cycloalkyl ring, a 4 to 6-membered heterocyclicring; a phenyl or a 5 or 6-membered heteroaryl ring, resulting in abicyclic system wherein the two rings are in a spiro, fused or bridgedrelationship, wherein said 4 to 6-membered heterocycle or said 5 or6-membered heteroaryl ring contains up to three heteroatomsindependently selected from N, O or S; and wherein said C₃₋₈ cycloalkylring, 4 to 6-membered heterocyclic ring, phenyl or 5 or 6-memberedheteroaryl ring is optionally and independently substituted by up to 3instances of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,oxo, —C(O)O(C₁₋₄ alkyl), —C(O)OH, —C(O)NH₂, —NR″(CO)O(C₁₋₄ alkyl), —OHor halogen; and R″ is hydrogen or a C₁₋₂ alkyl.

In those embodiments when one of R¹ or R² is the C₃₋₈ cycloalkyl ring, 4to 8-membered heterocyclic ring or 5 or 6-membered heteroarylsubstituted with up to 5 instances of R^(5f), two of the instances ofR^(5f) attached to the same or different ring atoms of said R¹ or R²,together with said atom or atoms, form a C₃₋₈ cycloalkyl ring, a 4 to6-membered heterocyclic ring, a phenyl or a 5 or 6-membered heterocyclicring, resulting in a bicyclic system wherein the two rings are in aspiro, fused or bridged relationship, wherein said 4 to 6-memberedheterocycle or said 5 or 6-membered heterocyclic ring contains up to tworing heteroatoms independently selected from N, O or S; and wherein saidC₃₋₈ cycloalkyl ring, 4 to 6-membered heterocyclic ring, phenyl or 5 or6-membered heterocyclic ring is optionally substituted by up to 2instances of C₁₋₄ alkyl, C₁₋₄ haloalkyl, oxo, —(CO)O(C₁₋₄ alkyl),—NR′(CO)O(C₁₋₄ alkyl) or halogen; wherein R′ is hydrogen or a C₁₋₂alkyl.In some embodiments, the two J^(D) groups attached to two vicinal ring Datoms, taken together with said two vicinal ring D atoms, may optionallyform a 5 to 6-membered heterocycle or a 5-membered heteroaryl ring thatis fused to ring D; wherein said 5 to 6-membered heterocycle or said5-membered ring heteroaryl contains from 1 to 3 heteroatomsindependently selected from N, O or S; and wherein said 5 to 6-memberedheterocycle or said 5-membered heteroaryl ring is optionally andindependently substituted by up to 3 instances of oxo or —(Y)—R⁹, andR^(Y) is defined as above.

In some embodiments of the first aspect, at least one of the twoinstances of X¹ and X² is N. In other embodiments, only one instance ofX¹ and X² is N and the other one is C. In still other embodiments, X² isC on ring D and is optionally substituted with J^(D).

In some embodiments of the compounds of Formula I′, the compound isrepresented by Formula IV′a:

J^(A) is selected from hydrogen, halogen, methyl, hydroxyl, methoxy,trifluoromethyl, trifluoromethoxy or —NR^(a)R^(b); in some of theseembodiments, R^(a) and R^(b) are each independently selected fromhydrogen, C₁₋₆ alkyl or a 3-6 cycloalkyl ring; alternatively, R^(a) andR^(b), together with the nitrogen atom to which they are both attached,may form a 4-8 membered heterocyclic ring or a 5-membered heteroarylring optionally containing up to two additional heteroatoms selectedfrom N, O and S; wherein each of said 4-8 membered heterocyclic ring and5-membered heteroaryl ring is optionally and independently substitutedby up to 6 instances of fluorine; J^(D) is selected from hydrogen orfluorine; and R¹ and R² are as defined supra.

In other embodiments of the compounds of Formula I′, the compound isrepresented by Formula II′b:

In some of these embodiments, ring B is a phenyl. In other embodiments,ring B is a 5 or 6-membered heteroaryl ring, containing 1 or 2 ringheteroatoms selected from N, O or S.

In some embodiments of the compounds of Formula II′b, X² on ring D iscarbon, optionally substituted by J^(D). In other embodiments, X² onring D is nitrogen.

In some embodiments of the compounds of Formula II′b, each J^(D) isindependently selected from J^(A), halogen, a C₁₋₆ aliphatic,—N(R^(D))₂, —N(R^(d))COR^(D), —N(R^(d))COOR^(D), —OR^(D),—N(R^(d))SO₂R^(D), or an optionally substituted C₃₋₈ cycloaliphaticring. In other embodiments, o is 2 and each J^(D) is independentlyselected from a halogen atom or —N(R^(D))₂, —N(R^(d))COR^(D), —OH,—N(R^(d))COOR^(D) or —N(R^(d))SO₂R^(D). In still other embodiments, o is2 and one instance of J^(D) is fluoro or chloro and the other instanceof J^(D) is —OH. In further embodiments of Formula II′b, o is 2 and oneinstance of J^(D) is —NH₂ and the other one is independently selectedfrom —N(R^(D))₂, wherein at least one instance of R^(D) is not hydrogen,or is —NHCOR^(D), —N(R^(d))COOR^(D) or —N(R^(d))SO₂R^(D). In yet otherembodiments, o is 2 and one instance of J^(D) is independently selectedfrom —N(R^(D))₂ or —NHCOR^(D) and the other instance of J^(D) isselected from fluoro or chloro. In still other embodiments, o is 1 andJ^(D) is amino.

In some embodiments of the compounds of Formula I′ or Formula II′b, thecompound is represented by one of Formula III′b or III′c:

In other embodiments of the compounds of Formula I′ or Formula II′b, thecompound is represented by Formula IV′b or Formula IV′c:

In some embodiments of the compounds of Formula IV′b or Formula IV′c, X²is nitrogen and the moiety —NR₁R₂ is absent. In other embodiments, X² iscarbon and the moiety —NR₁R₂ is present.

In some embodiments of any one of the above depicted Formulae wherein Wis ring B, the compound is represented by Formula V′b:

wherein, J^(A) is selected from hydrogen, halogen, methyl, hydroxyl,methoxy, trifluoromethyl, trifluoromethoxy or —NR^(a)R^(b); in some ofthese embodiments, R^(a) and R^(b) are each independently selected fromhydrogen, C₁₋₆ alkyl or a 3-6 cycloalkyl ring; alternatively, in otherembodiments, R^(a) and R^(b), together with the nitrogen atom to whichthey are both attached, may form a 4-8 membered heterocyclic ring or a5-membered heteroaryl ring optionally containing up to two additionalheteroatoms selected from N, O and S; wherein each of said 4-8 memberedheterocyclic ring and 5-membered heteroaryl ring is optionally andindependently substituted by up to 6 instances of fluorine; and J^(D) iseither absent or is fluorine.

In some embodiments of the compounds of Formula I′ or Formula II′b, ringB is phenyl. In other embodiments of the compounds of Formula I′ orFormula II′b, ring B is a 6-membered heteroaryl ring. In some of theseembodiments, n is an integer selected from 1, 2, or 3 and each J^(B) isindependently selected from halogen, a C₁₋₆ aliphatic or —OR^(B). Inother embodiments, each J^(B) is independently selected from halogen. Inother embodiments, each J^(B) is independently selected from fluoro orchloro. In still other embodiments, J^(B) is fluoro. In furtherembodiments, J^(B) is methyl or ethyl. In yet other embodiments, n is 1.In some of these embodiments in which n is 1, J^(B) is selected fromhalogen. In other embodiments, J^(B) is fluoro or chloro. In still otherembodiments, J^(B) is fluoro.

In other embodiments of Formula I′ or Formula II′b, at least one J^(B)is ortho to the attachment of the methylene linker between ring B andring A. In some of these embodiments in which at least one J^(B) isortho to the attachment of the methylene linker between ring B and ringA, the at least one J^(B) that is ortho is independently selected fromhalogen. In other embodiments, the at least one J^(B) is independentlyselected from fluoro or chloro. In still other embodiments, the at leastone J^(B) is fluoro. In yet other embodiments, n is 1 and the at leastone J^(B) ortho to the attachment of the methylene linker between ring Band ring A is fluoro.

In other embodiments of the compounds of Formula I′ or Formula II′b,ring B is a 6-membered heteroaryl ring. In some of these embodiments,ring B is a pyridyl ring. In other embodiments, ring B is a pyrimidinylring.

In some embodiments of the compounds of Formula I′, or Formula II′a, orFormula II′b, or Formula III′b or Formula III′c, o is an integerselected from 1, 2, and 3. In some of these embodiments in which o isselected from 1, 2, and 3, each J^(D) is independently selected fromhalogen, a C₁₋₆ aliphatic, —N(R^(D))₂, —N(R^(d))C(O)R^(D),—N(R^(d))C(O)OR^(D), —N(R^(d))C(O)N(R^(D))₂, —SO₂R^(D), —SO₂N(R^(D))₂,—N(R^(d))SO₂R^(D), —OR^(D) or an optionally substituted C₃₋₈cycloaliphatic ring.

In other embodiments of the compounds of Formula I′ or Formula II′a, orFormula II′b, or Formula III′b or Formula III′c, o is 1 or 2 and eachJ^(D) is independently selected from a halogen atom or —N(R^(D))₂,—N(R^(d))COR^(D), —OH, —N(R^(d))COOR^(D), or —N(R^(d))SO₂R^(D). In someof these embodiments wherein o is 1 or 2, each R^(d) is independentlyselected from hydrogen or C₁₋₄ alkyl. In other embodiments when o is 1or 2, at least one instance of J^(D) is independently selected fromfluoro, chloro, oxo, hydroxyl or amino.

In some embodiments of the compounds of Formula I′ or Formula II′a, thecompounds is represented by one of Formulae Va or VI′a:

wherein ring E is a 5 or 6-membered heterocyclic ring, containing up to3 heteroatoms selected from N, O and S; and wherein each J^(E) isindependently selected from oxo or —(Y)—R⁹.

In some of the embodiments of the compounds of Formula I′ or FormulaII′b, the compound is represented by one of Formulae VI′b or FormulaVII′b:

wherein ring E is a 5 or 6-membered heterocyclic ring, containing up to3 heteroatoms selected from N, O and S; and wherein each J^(E) isindependently selected from oxo or —(Y)—R⁹.

In some of the embodiments of the compounds of Formula V′a, FormulaVI′a, Formula VI′b or Formula VII′b, J^(A) is selected from halogen,—NH₂, —OH, or hydrogen.

In some of the embodiments of the compounds of Formula V′a, FormulaVI′a, Formula VI′b or Formula VII′b, ring E is a heterocyclic ringcontaining one nitrogen ring atom and at least one instance of J^(E) isoxo. In some of these embodiments, one J^(E) is oxo and two otherinstances of J^(E) are independently selected from —(Y)—R⁹.

In other embodiments of the compounds of Formula V′a, Formula VI′a,Formula VI′b or Formula VII′b, each —(Y)—R⁹ is independently selectedfrom a C₁₋₆ alkyl; a 5 or 6-membered heteroaryl ring containing between1 and 3 heteroatoms independently selected from N, O or S and optionallysubstituted by one or more instances of C₁₋₆ alkyl or halogen; and—C(O)NH—R¹⁰. In some of these embodiments, R¹⁰ is a C₃₋₆ cycloalkylring.

In some embodiments of the compounds of Formula I′ or Formula II′a, thecompound is represented by Formula VII′a:

In these embodiments, ring E is a 5 or 6-membered heterocyclic ring,containing up to 3 heteroatoms selected from N, O and S; and each J^(E)is independently selected from oxo or —(Y)—R⁹.

In some of the compounds of Formula I′ or Formula II′b, the compound isrepresented by Formula VIII′b:

wherein ring E is a 5 or 6-membered heterocyclic ring, containing up to3 heteroatoms selected from N, O and S; and each J^(E) is independentlyselected from oxo or —(Y)—R⁹.

In some of the embodiments of the compounds of Formula VII′a and FormulaVIII′b, one instance of J^(E) is oxo and two other instances of J^(E)are independently selected from C₁₋₆ alkyl; a 5 or 6-membered heteroarylring, containing between 1 and 3 heteroatoms independently selected fromN, O or S and optionally substituted by one or more instances of C₁₋₆alkyl or halogen; and —(CO)NH—R¹⁰. In some of these embodiments, R¹⁰ isa C₃₋₆ cycloalkyl ring.

In some of the embodiments of the compounds of Formula I′ or FormulaVII′a, the compound is represented by Formula VIII′a or Formula VIII′d:

To be perfectly clear, both —(Y)—R⁹ substituents may be attached to anyof the available ring carbons, but are attached to the same carbon.

In some embodiments of the compounds of Formula I′ or Formula VIII′b,the compound is represented by Formula XIX′b or Formula XIX′d:

As above, both —(Y)—R⁹ substituents may be attached to any of theavailable ring carbons, but are attached to the same carbon.

In some of the compounds of Formula I′, the compound is represented byone of Formulae XIX′a or X′a,

In these embodiments, each J^(A) is independently selected from —NH₂ orhydrogen. In some embodiments, each J^(D) is either absent or is halogenwhen R¹ and R² are not both hydrogen. In other embodiments, R¹ and R²are both simultaneously hydrogen, and each J^(D) is independentlyselected from —C(O)R^(D), —C(O)OR^(D), —OC(O)R^(D), —C(O)N(R^(D))₂,—N(R^(D))₂, —N(R^(d))C(O)R^(D), —N(R^(d))C(O)OR^(D),—N(R^(d))C(O)N(R^(D))₂, —OC(O)N(R^(D))₂, —SO₂R^(D), —SO₂N(R^(D))₂ or—N(R^(d))SO₂R^(D).

In some of the compounds of Formula I′, the compound is represented byone of Formulae X′b or XI′b:

In these embodiments, each J^(A) is independently selected from —NH₂ orhydrogen. In some embodiments, each J^(D) is either absent or is halogenwhen R¹ and R² are not both hydrogen. In other embodiments, R¹ and R²are both simultaneously hydrogen, and each J^(D) is independentlyselected from —C(O)R^(D), —C(O)OR^(D), —OC(O)R^(D), —C(O)N(R^(D))₂,—N(R^(D))₂, —N(R^(d))C(O)R^(D), —N(R^(d))C(O)OR^(D),—N(R^(d))C(O)N(R^(D))₂, —OC(O)N(R^(D))₂, —SO₂R^(D), —SO₂N(R^(D))₂ or—N(R^(d))SO₂R^(D).

In some of the embodiments of the compounds of Formula I′, Formula XIX′aFormula X′a, Formula X′b, or Formula XI′b, J^(D) is selected from —NH₂,—OH, and hydrogen.

In some embodiments, R^(C) is not a ring. In some of these embodiments,R^(C) is halogen, —CN, C₁₋₆ alkyl, —(C₁₋₆ alkyl)-R^(N), —COOR⁷, —COR⁷,—C(O)OR⁷, —C(O)N(R⁷)₂, —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁷, —N(R⁷)C(O)N(R⁷)₂,—N(R⁷)₂, —SO₂R⁷, —SO₂N(R⁷)₂, or —N(R⁷)SO₂R⁷. In some embodiments whenR^(C) is a C₁₋₆ alkyl or —(C₁₋₆ alkyl)-R^(N), the C₁₋₆ alkyl or the(C₁₋₆ alkyl) portion of the —(C₁₋₆ alkyl)-R^(N) moiety may be optionallyand independently substituted with up to 6 instances of fluoro and/or upto 2 instances of R^(7c). In other embodiments, R^(C) is —CN, C₁₋₆alkyl, —COR⁷, —C(O)OR⁷, —C(O)N(R⁷)₂, —N(R⁷)₂, —SO₂R⁷, or —SO₂N(R⁷)₂. Insome embodiments when R^(C) is a C₁₋₆ alkyl or —(C₁₋₆ alkyl)-R^(N), theC₁₋₆ alkyl or the (C₁₋₆ alkyl) portion of the —(C₁₋₆ alkyl)-R^(N) moietymay be optionally and independently substituted with up to 6 instancesof fluoro and/or up to 2 instances of R^(7c). In still otherembodiments, R^(C) is —COR⁷, —C(O)OR⁷, —C(O)N(R⁷)₂, —N(R⁷)₂, —SO₂R⁷ or—SO₂N(R⁷)₂.

In some embodiments, R^(C) is a ring.

The present invention is further directed to compounds of Formula I, orpharmaceutically acceptable salts thereof,

wherein:

-   X is selected from N, CH, C(C₁₋₄ alkyl), C(C₁₋₄haloalkyl), CCl and    CF;-   ring B is a phenyl or a 6-membered heteroaryl ring containing 1 or 2    ring nitrogen atoms, or ring B is a thiophene;-   n is 0 or an integer selected from 1 to 3;-   each J^(B) is independently selected from halogen, —CN, a C₁₋₆    aliphatic, —OR^(B) or a C₃₋₈ cycloaliphatic ring; wherein each of    said C₁₋₆ aliphatic and each of said C₃₋₈ cycloaliphatic group is    optionally substituted with up to 3 instances of halogen;-   each R^(B) is independently selected from hydrogen, a C₁₋₆ aliphatic    or a C₃₋₈ cycloaliphatic ring; wherein each of said R^(B) that is a    C₁₋₆ aliphatic and each of said R^(B) that is a C₃₋₈ cycloaliphatic    ring is optionally substituted with up to 3 instances of halogen;    J^(A) is selected from hydrogen, halogen, methyl, methoxy,    trifluoromethyl, trifluoromethoxy or —NR^(a)R^(b), wherein R^(a) and    R^(b) are each independently selected from hydrogen, C₁₋₆ alkyl or a    3-6 cycloalkyl ring;-   J^(D) is absent or selected from halogen, —CN, —CF₃, methoxy,    trifluoromethoxy, nitro, amino or methyl;-   R¹ and R², together with the nitrogen atom to which they are    attached, form a 4 to 8-membered heterocyclic ring or 5 or    6-membered heteroaryl ring; wherein said 4 to 8-membered    heterocyclic ring or 5 or 6-membered heteroaryl ring optionally    contains in addition to the nitrogen atom up to 3 ring heteroatoms    independently selected from N, O or S, and is optionally substituted    by up to 5 instances of R⁵; or-   alternatively, R¹ and R² are each independently selected from    hydrogen, C₁₋₆ alkyl, a C₃₋₈ cycloalkyl ring, a 4 to 8-membered    heterocyclic ring, a 5 or 6-membered heteroaryl or a C₁₋₆    alkyl-R^(Y); wherein each of said 4 to 8-membered heterocyclic ring    and each of said 5 or 6-membered heteroaryl ring contains up to 3    ring heteroatoms independently selected from N, O and S; and wherein    each of said C₁₋₆ alkyl, C₃₋₈ cycloalkyl ring, 4 to 8-membered    heterocyclic ring group, 5 or 6-membered heteroaryl and the C₁₋₆    alkyl portion of said C₁₋₆ alkyl-R^(Y) is optionally and    independently substituted with up to 5 instances of R^(5a); provided    that R¹ and R² are never simultaneously hydrogen; or-   alternatively, J^(D) and one of R¹ or R² can form a 5-6 membered    heterocyclic ring containing up to two heteroatoms selected from O,    N and S and optionally substituted with up to 3 instances of oxo or    —(Y)—R⁹;-   wherein Y is either absent or is a linkage in the form of a C₁₋₆    alkyl chain, optionally substituted by up to 6 instances of fluoro;-   each R⁹ is independently selected from hydrogen, fluoro, —CN, —OR¹⁰,    —SR¹⁰, —COR¹⁰, —OC(O)R¹⁰, —C(O)OR¹⁰, —C(O)N(R¹⁰)₂,    —C(O)N(R¹⁰)SO₂R¹⁰, —N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)C(O)OR¹⁰,    —N(R¹⁰)C(O)N(R¹⁰)₂, —N(R¹⁰)₂, —SO₂R¹⁰, —SO₂N(R¹⁰)₂,    —SO₂N(R¹⁰)COOR¹⁰, —SO₂N(R¹⁰)C(O)R¹⁰, —N(R¹⁰)SO₂R¹⁰, —(C═O)NHOR¹⁰, a    C₃₋₆ cycloalkyl ring, a 4-8-membered heterocyclic ring or a 5-6    membered heteroaroaryl ring; wherein each said 4 to 8-membered    heterocyclic ring or 5 to 6-membered heteroaromatic ring contains up    to 4 ring heteroatoms independently selected from N, O or S; and    wherein each of said C₃₋₆ cycloalkyl rings, each of said 4 to    8-membered heterocyclic rings and each of said 5 to 6-membered    heteroaromatic rings is optionally substituted with up to 3    instances of R¹¹;-   each R¹¹ is independently selected from halogen, C₁₋₆ alkyl, —CN,    —OR¹², —SR¹², —COR¹², —OC(O)R¹², —C(O)OR¹², —C(O)N(R¹²)₂,    —C(O)N(R¹²)SO₂R¹², —N(R¹²)C(O)R¹², —N(R¹²)C(O)OR¹²,    —N(R¹²)C(O)N(R¹²)₂, —N(R¹²)₂, —SO₂R¹², —SO₂N(R¹²)₂,    —SO₂N(R¹²)COOR¹², —SO₂N(R¹²)C(O)R¹², —N(R¹²)SO₂R¹² and —N═OR¹²;    wherein each of said C₁₋₆ alkyl is optionally and independently    substituted by up to 3 instances of fluoro, —OH, —O(C₁₋₄ alkyl),    phenyl and —O(C₁₋₄ fluoroalkyl);-   wherein each R¹⁰ is independently selected from hydrogen, a C₁₋₆    alkyl, phenyl, benzyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered    heterocyclic ring or a 5 or 6-membered heteroaryl ring, wherein each    5 or 6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring    contains up to 4 ring heteroatoms independently selected from N, O    and S; and wherein each of said C₁₋₆ alkyl, each said phenyl, each    said benzyl, each said C₃₋₈ cycloalkyl group, each said 4 to    7-membered heterocyclic ring and each 5 or 6-membered heteroaryl    ring is optionally and independently substituted with up to 3    instances of halogen, C₁₋₄ alkyl, C₁₋₄ (fluoroalkyl), —OH, —NH₂,    —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —COO(C₁₋₄ alkyl),    —O(C₁₋₄ alkyl), —O(C₁₋₄ fluoroalkyl) or oxo; and-   wherein each R¹² is independently selected from hydrogen, a C₁₋₆    alkyl, phenyl, benzyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered    heterocyclic ring or a 5 or 6-membered heteroaryl ring, wherein each    5 or 6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring    contains up to 4 ring heteroatoms independently selected from N, O    and S; and wherein each of said C₁₋₆ alkyl, each said phenyl, each    said benzyl, each said C₃₋₈ cycloalkyl group, each said 4 to    7-membered heterocyclic ring and each 5 or 6-membered heteroaryl    ring is optionally and independently substituted with up to 3    instances of halogen, C₁₋₄ alkyl, C₁₋₄ (fluoroalkyl), —OH, —NH₂,    —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —COO(C₁₋₄ alkyl),    —O(C₁₋₄ alkyl), —O(C₁₋₄ fluoroalkyl) or oxo;-   R^(Y) is selected from a C₃₋₈ cycloalkyl ring, a 4 to 8-membered    heterocyclic ring, phenyl, or a 5 to 6-membered heteroaromatic ring;    wherein each of said 4 to 8-membered heterocyclic ring or 5 to    6-membered heteroaromatic ring contains up to 4 ring heteroatoms    independently selected from N, O or S; and wherein each of said C₃₋₈    cycloalkyl ring, each of said 4 to 8-membered heterocyclic ring,    each of said phenyl, and each of said 5 to 6-membered heteroaromatic    ring is optionally substituted with up to 5 instances of R^(5c);-   each R^(5c) is independently selected from halogen, —CN, C₁₋₆ alkyl,    —OR^(6b), —SR^(6b), —COR^(6b), —OC(O)R^(6b), —C(O)OR^(6b),    —C(O)N(R^(6b))₂, —C(O)N(R^(6b))SO₂R^(6b), —N(R^(6b))C(O)R^(6b),    —N(R^(6b))C(O)OR^(6b), —N(R^(6b))C(O)N(R^(6b))₂, —N(R^(6b))₂,    —SO₂R^(6b), —SO₂N(R^(6b))₂, —SO₂N(R^(6b))COOR^(6b),    —SO₂N(R^(6b))C(O)R^(6b), —N(R^(6b))SO₂R^(6b), —(C═O)NHOR^(6b), a    C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclic ring, a 5 or    6-membered heteroaryl ring, phenyl, benzyl, an oxo group, or a    bicyclic group; wherein each of said 5 or 6-membered heteroaryl ring    and each of said 4 to 7-membered heterocyclic ring contains up to 4    ring heteroatoms independently selected from N, O and S; and wherein    each of said C₁₋₆ alkyl, each of said C₃₋₈ cycloalkyl ring, each of    said 4 to 7-membered heterocyclic ring, each of said 5 or 6-membered    heteroaryl ring, each of said benzyl and each of said phenyl group    is optionally and independently substituted with up to 3 instances    of halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂,    —CN, —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or    oxo; wherein said bicyclic group contains a first ring and a second    ring in a fused or bridged relationship, said first ring is a 4 to    7-membered heterocyclic ring, a 5 or 6-membered heteroaryl ring,    phenyl or benzyl, and said second ring is a phenyl ring or a 5 or    6-membered heteroaryl ring containing up to 3 ring heteroatoms    selected from N, O or S; and wherein said bicyclic group is    optionally and independently substituted by up to six instances of    halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂,    —CN, —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or    oxo;-   each R^(6b) is independently selected from hydrogen, a C₁₋₆ alkyl,    phenyl, benzyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered    heterocyclic ring or a 5 or 6-membered heteroaryl ring, wherein each    5 or 6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring    contains up to 4 ring heteroatoms independently selected from N, O    and S; and wherein each of said C₁₋₆ alkyl, each said phenyl, each    said benzyl, each said C₃₋₈ cycloalkyl group, each said 4 to    7-membered heterocyclic ring and each 5 or 6-membered heteroaryl    ring is optionally and independently substituted with up to 3    instances of halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl),    —N(C₁₋₄ alkyl)₂, —CN, —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl),    —O(C₁₋₄ haloalkyl) or oxo; or-   two instances of R^(5c) attached to the same or different ring atoms    of R^(Y), together with said ring atom or atoms, may form a C₃₋₈    cycloalkyl ring, a 4 to 6-membered heterocyclic ring; a phenyl or a    5 or 6-membered heteroaryl ring, resulting in a bicyclic system    wherein the two rings are in a spiro, fused or bridged relationship,    wherein said 4 to 6-membered heterocycle or said 5 or 6-membered    heteroaryl ring contains up to three heteroatoms independently    selected from N, O or S; and wherein said C₃₋₈ cycloalkyl ring, 4 to    6-membered heterocyclic ring, phenyl or a 5 or 6-membered heteroaryl    ring is optionally and independently substituted by up to 3    instances of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄    haloalkoxy, oxo, —C(O)O(C₁₋₄ alkyl), —C(O)OH, —NR″(CO)CO(C₁₋₄    alkyl), —OH or halogen; wherein R″ is hydrogen or a C₁₋₂ alkyl;-   each R^(5a) is independently selected from halogen, —CN, C₁₋₆ alkyl,    —OR^(6a), —SR^(6a), —COR^(6a), —OC(O)R^(6a), —C(O)OR^(6a),    —C(O)N(R^(6a))₂, —C(O)N(R^(6a))SO₂R^(6a), —N(R^(6a))C(O)R^(6a),    —N(R^(6a))C(O)OR^(6a), —N(R^(6a))C(O)N(R^(6a))₂, —N(R^(6a))₂,    —SO₂R^(6a), —SO₂N(R^(6a))₂, —SO₂N(R^(6a))COOR^(6a),    —SO₂N(R^(6a))C(O)R^(6a), —N(R^(6a))SO₂R^(6a), —(C═O)NHOR^(6a), a    C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclic ring, a 5 or    6-membered heteroaryl ring, phenyl, benzyl, an oxo group or a    bicyclic group; wherein each 5 or 6-membered heteroaryl ring or 4 to    7-membered heterocyclic ring contains up to 4 ring heteroatoms    independently selected from N, O and S, wherein each of said C₁₋₆    alkyl, C₃₋₈ cycloalkyl ring, 4 to 7-membered heterocyclic ring, 5 or    6-membered heteroaryl ring, benzyl or phenyl group is optionally and    independently substituted with up to 3 instances of halogen, C₁₋₄    alkyl, C₁₋₄ haloalkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂,    —CN, —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄haloalkyl) or    oxo; wherein said bicyclic group contains ring one and ring two in a    fused or bridged relationship, said ring one is a 4 to 7-membered    heterocyclic ring, a 5 or 6-membered heteroaryl ring, phenyl or    benzyl, and said ring two is a phenyl ring or a 5 or 6-membered    heteroaryl ring containing up to 3 ring heteroatoms selected from N,    O or S; and wherein said bicyclic group is optionally and    independently substituted by up to six instances of halogen, C₁₋₄    alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH,    —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo;-   each R^(6a) is independently selected from hydrogen, a C₁₋₆ alkyl,    phenyl, benzyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered    heterocyclic ring or a 5 or 6-membered heteroaryl ring, wherein each    of said C₁₋₆ alkyl, each of said phenyl, each of said benzyl, each    of said C₃₋₈ cycloalkyl group, each of said 4 to 7-membered    heterocyclic ring and each of said 5 or 6-membered heteroaryl ring    is optionally and independently substituted with up to 3 instances    of halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂,    —CN, —COOH, —C(O)NH₂, —C(O)N(C₁₋₆ alkyl)₂, —C(O)NH(C₁₋₆ alkyl),    —C(O)N(C₁₋₆ haloalkyl)₂, —C(O)NH(C₁₋₆ haloalkyl), C(O)N(C₁₋₆    alkyl)(C₁₋₆ haloalkyl), —COO(C₁₋₆ alkyl), —COO(C₁₋₆ haloalkyl),    —O(C₁₋₄ alkyl), —O(C₁₋₄haloalkyl) or oxo, wherein each of said 5 or    6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring    contains up to 4 ring heteroatoms independently selected from N, O    and S; or-   when one of R¹ or R² is the C₃₋₈ cycloalkyl ring, 4 to 8-membered    heterocyclic ring or 5 or 6-membered heteroaryl substituted with up    to 5 instances of R^(5a), two of the instances of R^(5a) attached to    the same or different ring atoms of said R¹ or R², together with    said atom or atoms, may optionally form a C₃₋₈ cycloalkyl ring, a 4    to 6-membered heterocyclic ring, a phenyl or a 5 or 6-membered    heterocyclic ring, resulting in a bicyclic system wherein the two    rings are in a spiro, fused or bridged relationship, wherein said 4    to 6-membered heterocycle or said 5 or 6-membered heterocyclic ring    contains up to two ring heteroatoms independently selected from N, O    or S; and wherein said C₃₋₈ cycloalkyl ring, 4 to 6-membered    heterocyclic ring, phenyl or 5 or 6-membered heterocyclic ring is    optionally substituted by up to 2 instances of C₁₋₄ alkyl, C₁₋₄    haloalkyl, oxo, —(CO)CO(C₁₋₄ alkyl), —NR′(CO)CO(C₁₋₄ alkyl) or    halogen; wherein R′ is hydrogen or a C₁₋₂ alkyl;-   each R⁵ is independently selected from halogen, —CN, C₁₋₆ alkyl,    —OR⁶, —SR⁶, —COR⁶, —OC(O)R⁶, —C(O)OR⁶, —C(O)N(R⁶)₂,    —C(O)N(R⁶)SO₂R⁶,—N(R⁶)C(O)R⁶, —N(R⁶)C(O)OR⁶, —N(R⁶)C(O)N(R⁶)₂,    —N(R⁶)₂, —SO₂R⁶, —SO₂N(R⁶)₂, —SO₂N(R⁶)COOR⁶, —SO₂N(R⁶)C(O)R⁶,    —N(R⁶)SO₂R⁶, —(C═O)NHOR⁶, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered    heterocyclic ring, a 5 or 6-membered heteroaryl ring, phenyl,    benzyl, an oxo group or a bicyclic group; wherein each of said 5 or    6-membered heteroaryl ring or 4 to 7-membered heterocyclic ring    contains up to 4 ring heteroatoms independently selected from N, O    and S; and wherein each of said C₁₋₆ alkyl, C₃₋₈ cycloalkyl ring, 4    to 7-membered heterocyclic ring, 5 or 6-membered heteroaryl ring,    benzyl or phenyl group is optionally and independently substituted    with up to 3 instances of halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄    alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄    alkyl), —O(C₁₋₄ haloalkyl) or oxo; wherein said bicyclic group    contains ring one and ring two in a fused or bridged relationship,    said ring one is a 4 to 7-membered heterocyclic ring, a 5 or    6-membered heteroaryl ring, phenyl or benzyl, and said ring two is a    phenyl ring or a 5 or 6-membered heteroaryl ring containing up to 3    ring heteroatoms selected from N, O or S; and wherein said bicyclic    group is optionally and independently substituted by up to six    instances of halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl),    —N(C₁₋₄ alkyl)₂, —CN, —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl),    —O(C₁₋₄ haloalkyl) or oxo;-   each R⁶ is independently selected from hydrogen, a C₁₋₆ alkyl,    phenyl, benzyl, a C₃₋₈ cycloalkyl ring or a 4 to 7-membered    heterocyclic ring, a 5 or 6-membered heteroaryl ring; wherein each    of said 5 or 6-membered heteroaryl ring or 4 to 7-membered    heterocyclic ring contains up to 4 ring heteroatoms independently    selected from N, O and S; and wherein each of said C₁₋₆ alkyl, each    of said phenyl, each of said benzyl, each of said C₃₋₈ cycloalkyl    group, each of said 4 to 7-membered heterocyclic ring and each of    said 5 or 6-membered heteroaryl ring is optionally and independently    substituted with up to 3 instances of halogen, C₁₋₄ alkyl, —OH,    —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —COO(C₁₋₄    alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo; or-   when R¹ and R² attached to the nitrogen atom form the 4 to    8-membered heterocyclic ring or 5 or 6-membered heteroaryl ring    substituted with up to 5 instances of R⁵, two of the instances of R⁵    attached to the same or different atoms of said ring, together with    said atom or atoms, may optionally form a C₃₋₈ cycloalkyl ring, a 4    to 6-membered heterocyclic ring; a phenyl or a 5 or 6-membered    heteroaryl ring, resulting in a bicyclic system wherein the two    rings of the bicyclic system are in a spiro, fused or bridged    relationship, wherein said 4 to 6-membered heterocycle or said 5 or    6-membered heteroaryl ring contains up to three ring heteroatoms    independently selected from N, O or S; and wherein said C₃₋₈    cycloalkyl ring, 4 to 6-membered heterocyclic ring, phenyl or 5 or    6-membered heteroaryl ring is optionally and independently    substituted by up to 3 instances of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄    alkoxy, C₁₋₄haloalkoxy, oxo, —C(O)O(C₁₋₄ alkyl), —C(O)OH,    —NR(CO)CO(C₁₋₄ alkyl), —OH or halogen; wherein R is hydrogen or a    C₁₋₂ alkyl;-   p is an integer selected from 0, 1 or 2;-   ring C is a monocyclic 5-membered heteroaryl ring containing up to 4    ring heteroatoms selected from N, O or S; wherein said monocyclic    5-membered heteroaryl ring is not a 1,3,5-triazinyl ring;-   each J^(C) is independently selected from halogen or a C₁₋₄    aliphatic optionally and independently substituted by up to 3    instances of C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, oxo, —C(O)O(C₁₋₄ alkyl),    —C(O)OH, —NR(CO)CO(C₁₋₄ alkyl), —OH or halogen; or-   alternatively, ring C is absent, p is 1, and J^(C) is selected from    halogen, —CN, C₁₋₆ alkyl, —OR⁷, —SR⁷, —COR⁷, —OC(O)R⁷, —C(O)OR⁷,    —C(O)N(R⁷)₂, —N(R⁷)C(O)R⁷, —N(R⁷)C(O)OR⁷, —N(R⁷)C(O)N(R⁷)₂, —N(R⁷)₂,    —SO₂R⁷, —SO₂N(R⁷)₂, —C(O)N(R⁷)SO₂R⁷, —SO₂N(R⁷)COOR⁷,    —SO₂N(R⁷)C(O)R⁷, —N(R⁷)SO₂R⁷, —(C═O)NHOR⁷ or an oxo group; wherein    C₁₋₆ alkyl is optionally and independently substituted with up to 6    instances of fluoro and up to 2 instances of —CN, —OR⁸, oxo,    —N(R⁸)₂, —N(R⁸)C(O)R⁸, —N(R⁸)C(O)OR⁸, —N(R⁸)C(O)N(R⁸)₂, —SO₂R⁸,    —SO₂N(R⁸)₂, —NHOR⁸, —SO₂N(R⁸)COOR⁸, —SO₂N(R⁸)C(O)R⁸, —N(R⁸)SO₂R⁸;-   wherein each R⁷ is independently selected from hydrogen, C₁₋₆ alkyl,    C₁₋₆ fluoroalkyl, a C₃₋₈ cycloalkyl ring, phenyl, a 4 to 7-membered    heterocyclic ring or a 5 or 6-membered heteroaryl ring; wherein each    of said 5 or 6-membered heteroaryl ring or 4 to 7-membered    heterocyclic ring contains up to 4 ring heteroatoms independently    selected from N, O and S; and wherein each of said C₁₋₆ alkyl, each    of said phenyl, each of said C₃₋₈ cycloalkyl group, each of said 4    to 7-membered heterocyclic ring and each of said 5 or 6-membered    heteroaryl ring is optionally and independently substituted with up    to 3 instances of halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl),    —N(C₁₋₄ alkyl)₂, —CN, —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl),    —O(C₁₋₄ haloalkyl) or oxo; and-   wherein, each R⁸ is independently selected from hydrogen, C₁₋₆    alkyl, C₁₋₆ fluoroalkyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered    heterocyclic ring or a 5 or 6-membered heteroaryl ring; wherein each    of said 5 or 6-membered heteroaryl ring or 4 to 7-membered    heterocyclic ring contains up to 4 ring heteroatoms independently    selected from N, O and S; and wherein each of said C₁₋₆ alkyl, each    of said phenyl, each of said C₃₋₈ cycloalkyl group, each of said 4    to 7-membered heterocyclic ring and each of said 5 or 6-membered    heteroaryl ring is optionally and independently substituted with up    to 3 instances of halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl),    —N(C₁₋₄ alkyl)₂, —CN, —COOH, —COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl),    —O(C₁₋₄ haloalkyl) or oxo.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, n is an integer selected from 1 or 2 and eachJ^(B) is independently selected from halogen, a C₁₋₄ alkyl or —OR^(B).In other embodiments, each J^(B) is independently selected from halogenatoms. In still other embodiments, each J^(B) is independently selectedfrom fluoro or chloro. In yet other embodiments, each J^(B) is fluoro.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, each J^(B) is a C₁₋₄ alkyl. In some of theseembodiments, J^(B) is ethyl or methyl. In some embodiments, J^(B) ismethyl.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, n is 1.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, n is 1 and each J^(B) is independentlyselected from halogen, a C₁₋₄ alkyl or —OR^(B). In some of theseembodiments, J^(B) is halogen. In some embodiments, J^(B) is chloro orfluoro. In other embodiments, J^(B) is fluoro. Alternatively, in otherembodiments, J^(B) is C₁₋₄ alkyl. In still other embodiments, J^(B) ismethyl or ethyl.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, at least one J^(B) is ortho to the attachmentof the methylene linker between ring B and the ring bearing X¹. In someof these embodiments, the at least one J^(B) is independently selectedfrom halogen atoms. In still other embodiments, each at least one J^(B)is independently selected from fluoro or chloro. In yet otherembodiments, each at least one J^(B) is fluoro. In other embodiments, nis 1 and the J^(B) ortho to the attachment of the methylene linkerbetween ring B and the ring bearing X¹ is fluoro.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, n is an integer selected from 1 or 2 and eachJ^(B) is independently selected from halogen, a C₁₋₄ alkyl or —OR^(B),wherein at least one J^(B) is ortho to the attachment of the methylenelinker between ring B and the ring bearing X¹. In some of theseembodiments, the halogen can be chloro or, preferably, fluoro. In otherembodiments, at least one J^(B) is halogen. Alternatively, at least oneJ^(B) is a C₁₋₄ alkyl, e.g., methyl or ethyl. In some of theseembodiments, n is 1. In some embodiments, the J^(B) ortho to theattachment of the methylene linker between ring B and the ring bearingX¹ is fluoro.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, n is 2 and each J^(B) is a halogen atom. Insome embodiments, each J^(B) is independently selected from chloro orfluoro. In other embodiments, one J^(B) is fluoro and the other J^(B) ischloro. In still other embodiments, each J^(B) is fluoro.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, ring B is phenyl. In some of theseembodiments, n is 1 or 2. In some of these embodiments, a J^(B) is orthoto the attachment of the methylene linker between ring B and the ringbearing X¹, and the J^(B) is halogen, e.g. chloro or, preferably,fluoro.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, ring B is a 6-membered heteroaryl ring or athiophene ring. In other embodiments, ring B is a pyridyl ring. In stillother embodiments, ring B is a pyrimidinyl ring. In yet otherembodiments, ring B is a thiophene ring.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, J^(D) is chloro, fluoro, or is absent. In someembodiments, J^(D) is fluoro.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, J^(A) is hydrogen.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, ring C is a monocyclic 5-membered heteroarylring containing 1 or 2 ring heteroatoms selected from N, O or S. In someof these embodiments, ring C is an oxazole or isoxazole ring. In some ofthese compounds, or pharmaceutically acceptable salts thereof, ring C isunsubstituted, and in yet other embodiments ring C is an unsubstitutedoxazole or isoxazole ring.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, X¹ is N. In some of these embodiments, ring Cis an oxazole or isoxazole ring. In other embodiments, ring C isunsubstituted, and in still embodiments, ring C is an unsubstitutedoxazole or isoxazole ring. In some of these embodiments, ring B isphenyl. In some of these embodiments, J^(B) is halogen, e.g., chloro or,preferably, fluoro. In other embodiments, there is a J^(B) ortho to themethylene bridge between the ring bearing X¹ and ring B. In some ofthese compounds, or pharmaceutically acceptable salts thereof, n is 1.In some of these compounds, or pharmaceutically acceptable saltsthereof, wherein n is 1, J^(B) is ortho to the methylene bridge betweenthe ring bearing X¹ and ring B. In some of these embodiments, J^(D) ishalogen, e.g., chloro or, preferably, fluoro.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, X¹ is N and p is 0. In some of theseembodiments, ring C is an oxazole or isoxazole ring. In some of theseembodiments, ring B is phenyl. In some of these embodiments, J^(B) ishalogen, e.g., chloro or, preferably, fluoro. In other embodiments,there is a J^(B) ortho to the methylene bridge between the ring bearingX¹ and ring B. In some of these embodiments, n is 1. In some of theseembodiments, n is 1, J^(B) is ortho to the methylene bridge between thering bearing X¹ and ring B, and J^(D) is halogen, e.g., chloro or,preferably, fluoro.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, X¹ is N and ring C is an isoxazolyl ring. Insome of these embodiments, ring B is phenyl. In some of theseembodiments, wherein ring B is phenyl, J^(B) is halogen, e.g., chloroor, preferably, fluoro. In other embodiments, wherein ring B is phenyl,n is 1. In still other embodiments, wherein ring B is phenyl and n is 1,J^(B) is halogen, preferably, fluoro. In yet other embodiments, whereinring B is phenyl, there is a J^(B) ortho to the methylene bridge betweenthe ring bearing X¹ and ring B. In yet other embodiments, wherein ring Bis phenyl, the J^(B) is ortho to the methylene bridge between the ringbearing X¹ and ring B, and J^(B) is preferably halogen, e.g., chloro orfluoro. In some of these compounds, or pharmaceutically acceptable saltsthereof, J^(D) is halogen. In some of these compounds, orpharmaceutically acceptable salts thereof, J^(D) is fluoro.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, X¹ is C with a substituent (resulting in, forinstance, CH, C(C₁₋₄ alkyl), C(C₁₋₄ haloalkyl), CCl or CF). In some ofthese embodiments, ring C is an oxazole or isoxazole ring. In some ofthese embodiments, ring C is unsubstituted, and in still otherembodiments, ring C is an unsubstituted oxazole or isoxazole ring. Insome of these embodiments, ring B is phenyl. In some of these compounds,or pharmaceutically acceptable salts thereof, J^(B) is halogen, e.g.,chloro or, preferably, fluoro. In some of these embodiments, there is aJ^(B) ortho to the methylene bridge between the ring bearing X¹ and ringB. In some of these compounds, or pharmaceutically acceptable saltsthereof, n is 1. In some of these compounds, or pharmaceuticallyacceptable salts thereof, wherein n is 1, J^(B) is ortho to themethylene bridge between the ring bearing X¹ and ring B. In some ofthese compounds, or pharmaceutically acceptable salts thereof, J^(D) ishalogen, e.g., chloro or, preferably, fluoro.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, X¹ is C with a substituent (resulting in, forinstance, CH, C(C₁₋₄ alkyl), C(C₁₋₄ haloalkyl), CCl or CF) and p is 0.In some of these embodiments, ring C is an oxazole or isoxazole ring. Insome of these embodiments, ring B is phenyl. In some of theseembodiments, J^(B) is halogen, e.g., chloro or, preferably, fluoro. Inother embodiments, there is a J^(B) ortho to the methylene bridgebetween the ring bearing X¹ and ring B. In some of these compounds, orpharmaceutically acceptable salts thereof, n is 1. In some of thesecompounds, or pharmaceutically acceptable salts thereof, wherein n is 1,J^(B) is ortho to the methylene bridge between the ring bearing X¹ andring B. In some of these compounds, or pharmaceutically acceptable saltsthereof, J^(D) is halogen, e.g., chloro or, preferably, fluoro.

In some embodiments of the compounds of Formula I, or pharmaceuticallyacceptable salts thereof, X¹ is C with a substituent (resulting in, forinstance, CH, C(C₁₋₄ alkyl), C(C₁₋₄ haloalkyl), CCl or CF) and ring C isan isoxazolyl group. In some of these embodiments, ring B is phenyl. Insome of these embodiments wherein ring B is phenyl, J^(B) is halogen,e.g., chloro or, preferably, fluoro. In other embodiments wherein ring Bis phenyl, n is 1. In still other embodiments wherein ring B is phenyland n is 1, J^(B) is halogen, preferably, fluoro. In yet otherembodiments wherein ring B is phenyl, there is a J^(B) ortho to themethylene bridge between the ring bearing X¹ and ring B. In yet otherembodiments wherein ring B is phenyl, the J^(B) is ortho to themethylene bridge between the ring bearing X¹ and ring B, and J^(B) ispreferably halogen, e.g., chloro or fluoro. In some of theseembodiments, J^(D) is halogen. In some of these compounds, orpharmaceutically acceptable salts thereof, J^(D) is fluoro.

The present invention is also directed to some embodiments of thecompounds of Formula I having a structure as depicted in Formulae IIa orIIb, or pharmaceutically acceptable salts thereof:

wherein each J^(B) is halogen; and ring C is an unsubstituted oxazole orisoxazole ring.

The present invention is also directed to some embodiments of thecompounds of Formula II having a structure as depicted in Formulae IIIato IIId, or pharmaceutically acceptable salts thereof:

wherein each J^(B) is halogen; and ring C is an unsubstituted oxazole orisoxazole ring.

The present invention is also directed to some embodiments of thecompounds of Formulae IIIa and IIIb having a structure as depicted inFormula IVa and Formula IVb, or pharmaceutically acceptable saltsthereof:

wherein each J^(B) is halogen;and ring F is a monocyclic or bicyclic 4 to 10-membered heterocyclicring or a monocyclic or bicyclic 5 to 10-membered heteroaryl ring;wherein said 4 to 10-membered heterocyclic ring or 5 to 10-memberedheteroaryl ring optionally contains up to 3 ring heteroatomsindependently selected from N, O or S, and is optionally andindependently substituted by up to 3 instances of R⁵.

In some of the embodiments of the compounds of Formula IVa or FormulaIVb, or pharmaceutically acceptable salts thereof, ring F is substitutedby:

(i) 3 instances of R⁵; wherein at least two of said instances are thesame, or

(ii) 0, 1 or 2 instances of R⁵; wherein, when ring F is substituted by 2instances of R⁵, then each of the instances of R⁵ is independentlyselected;

wherein each R⁵ is selected from fluoro, methyl, ethyl, methoxy,trifluoromethyl, trifluoromethoxy, hydroxyl, C₁₋₆ (hydroxy)alkyl, oxo,—CN, —O(C₁₋₆ alkyl)-COOR^(Z), —NH(C₁₋₆ alkyl)-COOR^(Z), —(C₁₋₆alkyl)-COOR^(Z), —COOR^(Z), —COR^(Z), —CON(R^(Z))₂, —NHCOOR^(Z),—NHCON(R^(Z))₂, —CONHSO₂R^(Z), —NHCOR^(Z), —NH(C₁₋₆ alkyl)-CON(R^(Z))₂,—N(R^(Z))₂, —SO₂R^(Z), —SO₂N(R^(Z))₂, —SO₂NHCOR^(Z), —SO₂NHCOOR^(Z),phenyl, benzyl, or a 5 or 6 membered heterocyclic or heteroaryl ring;wherein each of said phenyl, benzyl or 5-6 membered heteroaryl orheterocyclic ring is optionally substituted by 1 or 2 instances ofR^(a);

wherein each R^(Z) is independently selected from hydrogen, a C₃₋₆cycloalkyl, a C₁₋₆ alkyl, a C₁₋₆ fluoroalkyl; and

wherein each R^(Za) is independently selected from hydrogen, halogen, aC₃₋₆ cycloalkyl, a C₁₋₆ alkyl, a C₁₋₆ fluoroalkyl, oxo and —COOH.

In some of the embodiments of the compounds of Formula IVa or FormulaIVb, or pharmaceutically acceptable salts thereof, at least one instanceof R⁵ is a —COOH moiety or at least one instance of R⁵ is substituted bya —COOH moiety.

The present invention is also directed to some embodiments of thecompounds of Formula IVa or Formula IVb having a structure as depictedin Formula Va or Formula Vb, or pharmaceutically acceptable saltsthereof:

wherein F is a ring that includes the nitrogen attached to thepyrimidine, and wherein ring F is optionally and independently furthersubstituted by 1 or 2 instances of R⁵.

The present invention is also directed to some embodiments of thecompounds of Formula I having a structure as depicted in Formula VIa orFormula VIb, or pharmaceutically acceptable salts thereof:

wherein each J^(B) is halogen;

R¹ is hydrogen or C₁₋₆ alkyl;

and ring G is a monocyclic or bicyclic 4 to 10-membered heterocyclicring or a monocyclic or bicyclic 5 to 10-membered heteroaryl ring;wherein said 4 to 10-membered heterocyclic ring or 5 to 10-memberedheteroaryl ring optionally contains up to 3 ring heteroatomsindependently selected from N, O or S, and is optionally andindependently substituted by up to 3 instances of R^(5a).

In some of these compounds, or pharmaceutically acceptable saltsthereof, each R^(5a) is selected from fluoro, methyl, ethyl, methoxy,trifluoromethyl, trifluoromethoxy, hydroxyl, C₁₋₆ (hydroxy)alkyl, oxo,—CN, —O(C₁₋₆ alkyl)-COOR^(Zb), —NH(C₁₋₆ alkyl)-COOR^(Zb), —(C₁₋₆alkyl)-COOR^(Zb), —COOR^(Zb), —COR^(Zb), —CON(R^(Z))₂, —NHCOOR^(Zb),—NHCON(R^(Zb))₂, —CONHSO₂R^(Zb), —NHCOR^(Zb), —NH(C₁₋₆alkyl)-CON(R^(Z))₂, —N(R^(Zb))₂, —SO₂R^(Zb), —SO₂N(R^(Z))₂,—SO₂NHCOR^(Zb), —SO₂NHCOOR^(Zb), phenyl, benzyl, or a 5 or 6 memberedheterocyclic or heteroaryl ring; wherein each of said phenyl, benzyl or5-6 membered heteroaryl or heterocyclic ring is optionally substitutedby 1 or 2 instances of R^(Zc); wherein each R^(Zb) is independentlyselected from hydrogen, a C₁₋₄ alkyl, a C₁₋₄ fluoroalkyl; and whereineach R^(Zc) is independently selected from hydrogen, halogen, a C₁₋₄alkyl, a C₁₋₄ fluoroalkyl, oxo and —COOH.In some of these compounds, or pharmaceutically acceptable saltsthereof, at least one instance of R^(5a) is a —COOH moiety or at leastone instance of R^(5a) comprises a —COOH moiety.

The present invention is also directed to some embodiments of thecompounds of Formula VIa or Formula VIb having a structure as depictedin Formula VIIa or Formula VIIb, or pharmaceutically acceptable saltsthereof:

wherein ring G is optionally and independently further substituted by 1or 2 instances of R^(5a).

The present invention is also directed to some embodiments of thecompounds of Formula IIIa or Formula IIIc having a structure as depictedin Formula VIIIa or Formula VIIIb, or pharmaceutically acceptable saltsthereof:

wherein J^(B) is halogen; R¹ is hydrogen or C₁₋₆ alkyl; L is a C₁₋₆alkyl group optionally and independently substituted by up to threeinstances of R^(5a); and ring R^(Y) is a monocyclic or bicyclic 4 to10-membered heterocyclic ring or a monocyclic or bicyclic 5 to10-membered heteroaryl ring; wherein said 4 to 10-membered heterocyclicring or 5 to 10-membered heteroaryl ring optionally contains up to 3additional heteroatoms independently selected from N, O or S, and isoptionally and independently substituted by up to 3 instances of R^(5b).

The present invention is also directed to some embodiments of thecompounds of Formula VIIIa or Formula VIIIb having a structure asdepicted in one of Formulae IXa or IXb or Formulae Xa or Xb, orpharmaceutically acceptable salts thereof:

wherein in Formula IXa or Formula IXb, the linker L is furtheroptionally and independently substituted by up to two instances ofR^(5a); and in Formula Xa or Formula Xb, ring R^(Y) is furtheroptionally and independently substituted by up to two instances ofR^(5b).

The present invention is also directed to some embodiments of thecompounds of Formula IIIa or Formula IIIb having a structure as depictedin Formula XIa or Formula XIb, or pharmaceutically acceptable saltsthereof:

wherein J^(B) is halogen; R¹ is hydrogen or C₁₋₆ alkyl; and R² is a C₁₋₆alkyl group optionally and independently substituted by up to threeinstances of R^(5a).

In some embodiments, the compounds of Formula I are selected from thoselisted in Table 1A, Table 1B, Table 1C and Table 1D.

TABLE 1A

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-156

I-157

I-158

I-159

I-160

I-161

I-162

I-163

I-164

I-165

I-166

I-167

I-168

I-169

I-170

I-171

I-172

I-173

I-174

I-175

I-176

I-177

I-178

I-179

I-180

I-181

I-182

I-183

I-184

I-185

I-186

I-188

I-189

I-190

I-191

I-192

I-193

I-194

I-195

I-196

I-197

I-198

I-199

I-200

I-201

I-202

I-203

I-204

I-205

I-206

I-207

I-208

I-209

I-210

I-211

I-212

I-213

I-214

I-215

I-216

I-217

I-218

I-219

I-220

I-221

I-222

I-223

I-224

I-225

I-226

I-227

I-228

I-229

I-230

I-231

I-232

I-233

I-234

I-235

I-236

I-237

I-238

I-239

I-240

I-241

I-242

I-243

I-244

I-245

I-246

I-247

I-248

I-249

I-250

I-251

I-252

I-253

I-254

I-255

I-256

I-257

I-258

I-259

I-260

I-261

I-262

I-263

I-264

I-265

I-266

I-267

I-268

I-269

I-270

I-271

TABLE 1B

I-187

I-272

I-273

I-274

I-275

I-276

I-277

I-278

I-279

I-280

I-281

I-282

I-283

I-284

I-285

I-286

I-287

I-288

I-289

I-290

I-291

I-292

I-293

I-294

I-295

I-296

I-297

I-298

I-299

I-300

I-301

I-302

I-303

I-304

I-305

TABLE 1C

I-306

I-307

I-308

I-309

I-310

I-311

I-312

I-313

I-314

I-315

I-316

I-317

I-318

I-319

I-320

I-321

I-322

I-323

I-324

I-325

I-326

I-327

I-328

I-329

I-330

I-331

I-332

I-333

I-334

I-335

I-336

I-337

I-338

I-339

I-340

I-341

I-342

I-343

I-344

I-345

I-346

I-347

I-348

I-349

I-350

I-351

I-352

I-353

I-354

I-355

I-356

I-357

I-358

I-359

I-360

I-361

I-362

I-363

I-364

I-365

I-366

I-367

I-368

I-369

I-370

I-371

I-372

I-373

I-374

I-375

I-376

I-377

I-378

I-379

I-380

I-381

I-382

I-383

I-384

I-385

I-386

I-387

I-388

I-389

I-390

I-391

I-392

I-393

I-394

I-395

I-396

I-397

I-398

I-399

I-400

I-401

I-402

I-403

I-404

I-405

I-406

I-407

I-408

I-409

I-410

I-411

I-412

I-413

I-414

I-415

I-416

I-417

I-418

I-419

I-420

I-421

I-422

I-423

I-424

I-425

I-426

I-427

I-428

I-429

I-430

I-431

I-432

I-433

I-434

I-435

I-436

I-437

I-438

I-439

I-440

I-441

I-442

I-443

I-444

I-445

I-446

I-447

I-448

I-449

I-450

I-451

I-452

I-453

I-454

I-455

TABLE ID

I-456

I-457

I-458

I-459

I-460

I-461

I-462

I-463

I-464

I-465

I-466

I-467

I-468

I-469

I-470

I-471

I-472

I-473

I-474

I-475

I-476

I-477

I-478

I-479

I-480

I-481

I-482

I-483

I-484

I-485

I-486

I-487

I-488

I-489

I-490

I-491

I-492

I-493

I-494

I-495

I-496

I-497

I-498

I-499

I-500

I-501

I-502

I-503

I-504

I-505

I-506

I-507

I-508

I-509

I-510

I-511

I-512

I-513

I-514

I-515

I-516

I-517

I-518

I-519

I-520

I-521

I-522

I-523

I-524

I-525

I-526

I-527

I-528

I-529

I-530

I-531

I-532

I-533

I-534

I-535

I-536

I-537

I-538

I-539

I-540

I-541

I-542

I-543

I-544

I-545

I-546

I-547

I-548

I-549

I-550

I-551

I-552

I-553

I-554

I-555

I-556

I-557

I-558

I-559

I-560

I-561

I-562

I-563

I-564

I-565

I-566

I-567

I-568

I-569

I-570

I-571

I-572

I-573

I-574

I-575

I-576

I-577

I-578

I-579

I-580

I-581

I-582

I-583

I-584

I-585

I-586

I-587

I-588

I-589

I-590

I-591

I-592

I-593

I-594

I-595

I-596

I-597

I-598

I-599

I-600

I-601

I-602

I-603

I-604

I-605

I-606

I-607

I-608

I-609

I-610

I-611

I-612

I-613

I-614

I-615

I-616

I-617

I-618

I-619

I-620

I-621

I-622

I-623

I-624

I-625

I-626

I-627

I-628

I-629

I-630

I-631

I-632

I-633

I-634

Methods of Preparing the Compounds

The compounds of Formulae I to XI may be prepared according to theschemes and examples depicted and described below. Unless otherwisespecified, the starting materials and various intermediates may beobtained from commercial sources, prepared from commercially availablecompounds or prepared using well-known synthetic methods. Another aspectof the present invention is a process for preparing the compounds ofFormula I as disclosed herein.

General synthetic procedures for the compounds of this invention aredescribed below. The synthetic schemes are presented as examples and donot limit the scope of the invention in any way.

Step 1:

Dione enolate formation: To a solution of ketone A in THF cooled to −78°C., LiHMDS (e.g., 0.9 equiv, 1.0 M in toluene) was added dropwise viasyringe. The reaction was allowed to warm to 0° C., then charged withdiethyl oxalate (1.2 equiv). At this time, the reaction was warmed toroom temperature and stirred at that temperature until judged complete(e.g., using either TLC or LC/MS analysis). Once the reaction wascomplete (reaction time was typically 45 minutes), the product dioneenolate B was used “as-is” in Step 2, i.e., the cyclization step,without any further purification.

Step 2:

Pyrazole formation: Dione enolate B was diluted with ethanol andconsecutively charged with HCl (e.g., 3 equiv, 1.25 M solution inethanol) and arylhydrazine hydrate (e.g., 1.15 equiv). The reactionmixture was heated to 70° C. and stirred at this temperature untilcyclization was deemed complete (e.g., by LC/MS analysis, typically 30minutes). Once complete, the reaction mixture was treated carefully withsolid sodium bicarbonate (e.g., 4 equiv) and diluted withdichloromethane and water. Layers were separated, and aqueous layer wasfurther diluted with water before extraction with dichloromethane (3×).The combined organics were washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo. The resulting pyrazole C was thenpurified by SiO₂ chromatography using an appropriate gradient of EtOAcin hexanes.

Step 3:

Amidine formation: To a suspension of NH₄Cl (e.g., 5 equiv) in toluenecooled to 0° C. was added AlMe₃ (e.g., 5 equiv, 2.0 M solution intoluene) dropwise via syringe. The reaction was allowed to warm to roomtemperature, and stirred at this temperature until no more bubbling wasobserved. Pyrazole C was added in 1 portion to the reaction mixture,heated to 110° C., and stirred at this temperature until judged complete(e.g., using either TLC or LC/MS analysis). Once complete, the reactionwas cooled, treated with excess methanol, and stirred vigorously for 1hour at room temperature. The thick slurry was filtered, and theresulting solid cake was washed with methanol. The filtrate wasconcentrated in vacuo, and the resulting solids were re-suspended in anethyl acetate:isopropyl alcohol=5:1 solvent mixture. The reaction wasfurther treated with saturated sodium carbonate solution, and stirredfor 10 minutes before the layers are separated. The aqueous layer wasextracted with the ethyl acetate:isopropyl alcohol=5:1 solvent mixture(3×), and the combined organics were washed with brine. The organicswere further dried over MgSO₄, filtered, and the solvent removed invacuo. The product amidine D was used as-is in subsequent steps withoutfurther purification.

Step 4:

Pyrimidone formation: Amidine D was suspended in ethanol, and stirredvigorously at 23° C. to encourage full solvation. The reaction wasfurther treated with sodium 3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olate(e.g., 3 equiv.), and the flask was equipped with a reflux condenser.The reaction was placed into a pre-heated oil bath maintained at 90° C.and stirred until full consumption of starting material was observed onthe LC/MS (reaction times were typically 1 h). The contents were cooledto 23° C., and the reaction mixture acidified with HCl (e.g., 3 equiv.,1.25M solution in EtOH). The mixture was stirred for 30 minutes, and themajority of the solvent was removed in vacuo. Contents were re-suspendedin ether and water (1:1 mixture), and the resulting slurry was stirredfor 20 min. The suspension was vacuum filtered, and the solid cake wasrinsed with additional water and ether and dried on high vacuumovernight. The resulting pyrimidone E was used as-is in subsequent stepswithout further purification.

A solution of amino nucleophile (3 equiv.), triethylamine (10 equiv.),and Intermediate 1 (1 equiv.) was stirred in dioxane and water (2:1ratio) at 90° C. until complete consumption of starting material wasobserved by LC/MS. The solution was diluted with aqueous 1N hydrochloricacid and dichloromethane. The layers were then separated and the aqueouslayer was extracted with dichloromethane. The organics were combined,dried over magnesium sulfate, filtered, and the solvent was removed invacuo. Purification yielded the desired product.

A mixture of Intermediate 2 (this intermediate was described inpreviously published patent application WO2012/3405 A1; 1 equivalent)and carboxylic acid (1.1 equivalent) in N,N-dimethylformamide wastreated with triethylamine (4 equivalent) followed by a 50% in ethylacetate solution of propylphosphonic anhydride (T3P, 1.4 equivalent).The reaction was heated to 80° C. for 24 h, after which the reaction wasdiluted with water and 1N hydrochloric acid solution. Contents wereextracted with dichloromethane, then ethyl acetate. The combined organiclayers were dried over sodium sulfate, filtered, and concentrated invacuo. Purification yielded the desired product.

Pharmaceutically Acceptable Salts of the Invention.

The phrase “pharmaceutically acceptable salt,” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofFormula I or Formula I′. The pharmaceutically acceptable salts of acompound of Formula I or Formula I′ are used in medicine. Salts that arenot pharmaceutically acceptable may, however, be useful in thepreparation of a compound of Formula I or Formula I′ or of theirpharmaceutically acceptable salts. A pharmaceutically acceptable saltmay involve the inclusion of another molecule such as an acetate ion, asuccinate ion or other counter ion. The counter ion may be any organicor inorganic moiety that stabilizes the charge on the parent compound.Furthermore, a pharmaceutically acceptable salt may have more than onecharged atom in its structure. Instances where multiple charged atomsare part of the pharmaceutically acceptable salt can have multiplecounter ions. Hence, a pharmaceutically acceptable salt can have one ormore charged atoms and/or one or more counter ion.

Pharmaceutically acceptable salts of the compounds described hereininclude those derived from the compounds with inorganic acids, organicacids or bases. In some embodiments, the salts can be prepared in situduring the final isolation and purification of the compounds. In otherembodiments the salts can be prepared from the free form of the compoundin a separate synthetic step.

When a compound of Formula I or Formula I′ is acidic or contains asufficiently acidic bioisostere, suitable “pharmaceutically acceptablesalts” refers to salts prepared form pharmaceutically acceptablenon-toxic bases including inorganic bases and organic bases. Saltsderived from inorganic bases include aluminum, ammonium, calcium,copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc and the like. Particular embodiments includeammonium, calcium, magnesium, potassium and sodium salts. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as arginine, betaine, caffeine, choline, N,N.sup.1-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine tripropylamine, tromethamineand the like.

When a compound of Formula I or Formula I′ is basic or contains asufficiently basic bioisostere, salts may be prepared frompharmaceutically acceptable non-toxic acids, including inorganic andorganic acids. Such acids include acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Particular embodiments include citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric and tartaric acids. Other exemplary saltsinclude, but are not limited, to sulfate, citrate, acetate, oxalate,chloride, bromide, iodide, nitrate, bisulfate, phosphate, acidphosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate,oleate, tannate, pantothenate, bitartrate, ascorbate, succinate,maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate,formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

The preparation of the pharmaceutically acceptable salts described aboveand other typical pharmaceutically acceptable salts is more fullydescribed by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977:66:1-19, incorporated here by reference in its entirety.

In addition to the compounds described herein, their pharmaceuticallyacceptable salts may also be employed in compositions to treat orprevent the herein identified disorders.

Pharmaceutical Compositions and Methods of Administration.

The compounds herein disclosed, and their pharmaceutically acceptablesalts thereof may be formulated as pharmaceutical compositions or“formulations”.

A typical formulation is prepared by mixing a compound of Formula I orFormula I′, or a pharmaceutically acceptable salt thereof, and acarrier, diluent or excipient. Suitable carriers, diluents andexcipients are well known to those skilled in the art and includematerials such as carbohydrates, waxes, water soluble and/or swellablepolymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents,water, and the like. The particular carrier, diluent or excipient usedwill depend upon the means and purpose for which a compound of Formula Iand Formula I′ is being formulated. Solvents are generally selectedbased on solvents recognized by persons skilled in the art as safe(GRAS-Generally Regarded as Safe) to be administered to a mammal. Ingeneral, safe solvents are non-toxic aqueous solvents such as water andother non-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG400, PEG300), etc. and mixtures thereof. Theformulations may also include other types of excipients such as one ormore buffers, stabilizing agents, antiadherents, surfactants, wettingagents, lubricating agents, emulsifiers, binders, suspending agents,disintegrants, fillers, sorbents, coatings (e.g. enteric or slowrelease) preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of Formula I and Formula I′ or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., acompound of Formula I and Formula I′, a pharmaceutically acceptable saltthereof, or a stabilized form of the compound, such as a complex with acyclodextrin derivative or other known complexation agent) is dissolvedin a suitable solvent in the presence of one or more of the excipientsdescribed above. A compound having the desired degree of purity isoptionally mixed with pharmaceutically acceptable diluents, carriers,excipients or stabilizers, in the form of a lyophilized formulation,milled powder, or an aqueous solution. Formulation may be conducted bymixing at ambient temperature at the appropriate pH, and at the desireddegree of purity, with physiologically acceptable carriers. The pH ofthe formulation depends mainly on the particular use and theconcentration of compound, but may range from about 3 to about 8. Whenthe agent described herein is a solid amorphous dispersion formed by asolvent process, additives may be added directly to the spray-dryingsolution when forming the mixture such as the additive is dissolved orsuspended in the solution as a slurry which can then be spray dried.Alternatively, the additives may be added following spray-drying processto aid in the forming of the final formulated product.

The compound of Formula I and Formula I′ or a pharmaceuticallyacceptable salt thereof is typically formulated into pharmaceuticaldosage forms to provide an easily controllable dosage of the drug and toenable patient compliance with the prescribed regimen. Pharmaceuticalformulations of a compound of Formula I and Formula I′, or apharmaceutically acceptable salt thereof, may be prepared for variousroutes and types of administration. Various dosage forms may exist forthe same compound, since different medical conditions may warrantdifferent routes of administration.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thesubject treated and the particular mode of administration. For example,a time-release formulation intended for oral administration to humansmay contain approximately 1 to 1000 mg of active material compoundedwith an appropriate and convenient amount of carrier material which mayvary from about 5 to about 95% of the total compositions(weight:weight). The pharmaceutical composition can be prepared toprovide easily measurable amounts for administration. For example, anaqueous solution intended for intravenous infusion may contain fromabout 3 to 500 μg of the active ingredient per milliliter of solution inorder that infusion of a suitable volume at a rate of about 30 mL/hr canoccur. As a general proposition, the initial pharmaceutically effectiveamount of the inhibitor administered will be in the range of about0.01-100 mg/kg per dose, namely about 0.1 to 20 mg/kg of patient bodyweight per day, with the typical initial range of compound used being0.3 to 15 mg/kg/day.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician. The therapeutically or pharmaceutically effectiveamount of the compound to be administered will be governed by suchconsiderations, and is the minimum amount necessary to ameliorate, cureor treat the disease or disorder or one or more of its symptoms.

The pharmaceutical compositions of Formula I and Formula I′ will beformulated, dosed, and administered in a fashion, i.e., amounts,concentrations, schedules, course, vehicles, and route ofadministration, consistent with good medical practice. Factors forconsideration in this context include the particular disorder beingtreated, the particular mammal being treated, the clinical condition ofthe individual patient, the cause of the disorder, the site of deliveryof the agent, the method of administration, the scheduling ofadministration, and other factors known to medical practitioners, suchas the age, weight, and response of the individual patient.

The term “prophylactically effective amount” refers to an amounteffective in preventing or substantially lessening the chances ofacquiring a disease or disorder or in reducing the severity of thedisease or disorder before it is acquired or reducing the severity ofone or more of its symptoms before the symptoms develop. Roughly,prophylactic measures are divided between primary prophylaxis (toprevent the development of a disease) and secondary prophylaxis (wherebythe disease has already developed and the patient is protected againstworsening of this process).

Acceptable diluents, carriers, excipients, and stabilizers are thosethat are nontoxic to recipients at the dosages and concentrationsemployed, and include buffers such as phosphate, citrate, and otherorganic acids; antioxidants including ascorbic acid and methionine;preservatives (such as octadecyldimethylbenzyl ammonium chloride;hexamethonium chloride; benzalkonium chloride, benzethonium chloride;phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol);proteins, such as serum albumin, gelatin, or immunoglobulins;hydrophilic polymers such as polyvinylpyrrolidone; amino acids such asglycine, glutamine, asparagine, histidine, arginine, or lysine;monosaccharides, disaccharides, and other carbohydrates includingglucose, mannose, or dextrins; chelating agents such as EDTA; sugarssuch as sucrose, mannitol, tretralose or sorbitol; salt-formingcounter-ions such as sodium; metal complexes (e.g. Zn-proteincomplexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ orpolyethylene glycol (PEG). The active pharmaceutical ingredients mayalso be entrapped in microcapsules prepared, for example, bycoacervation techniques or by interfacial polymerization, e.g.,hydroxymethylcellulose or gelatin-microcapsules andpoly-(methylmethacylate) microcapsules, respectively; in colloidal drugdelivery systems (for example, liposomes, albumin microspheres,microemulsions, nano-particles and nanocapsules) or in macroemulsions.Such techniques are disclosed in Remington's: The Science and Practiceof Pharmacy, 21^(st) Edition, University of the Sciences inPhiladelphia, Eds., 2005 (hereafter “Remington's”).

“Controlled drug delivery systems” supply the drug to the body in amanner precisely controlled to suit the drug and the conditions beingtreated. The primary aim is to achieve a therapeutic drug concentrationat the site of action for the desired duration of time. The term“controlled release” is often used to refer to a variety of methods thatmodify release of drug from a dosage form. This term includespreparations labeled as “extended release”, “delayed release”, “modifiedrelease” or “sustained release”. In general, one can provide forcontrolled release of the agents described herein through the use of awide variety of polymeric carriers and controlled release systemsincluding erodible and non-erodible matrices, osmotic control devices,various reservoir devices, enteric coatings and multiparticulate controldevices.

“Sustained-release preparations” are the most common applications ofcontrolled release. Suitable examples of sustained-release preparationsinclude semipermeable matrices of solid hydrophobic polymers containingthe compound, which matrices are in the form of shaped articles, e.g.films, or microcapsules. Examples of sustained-release matrices includepolyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate),or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919),copolymers of L-glutamic acid and gamma-ethyl-L-glutamate,non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolicacid copolymers, and poly-D-(−)-3-hydroxybutyric acid.

“Immediate-release preparations” may also be prepared. The objective ofthese formulations is to get the drug into the bloodstream and to thesite of action as rapidly as possible. For instance, for rapiddissolution, most tablets are designed to undergo rapid disintegrationto granules and subsequent deaggregation to fine particles. Thisprovides a larger surface area exposed to the dissolution medium,resulting in a faster dissolution rate.

Agents described herein can be incorporated into an erodible ornon-erodible polymeric matrix controlled release device. By an erodiblematrix is meant aqueous-erodible or water-swellable or aqueous-solublein the sense of being either erodible or swellable or dissolvable inpure water or requiring the presence of an acid or base to ionize thepolymeric matrix sufficiently to cause erosion or dissolution. Whencontacted with the aqueous environment of use, the erodible polymericmatrix imbibes water and forms an aqueous-swollen gel or matrix thatentraps the agent described herein. The aqueous-swollen matrix graduallyerodes, swells, disintegrates or dissolves in the environment of use,thereby controlling the release of a compound described herein to theenvironment of use. One ingredient of this water-swollen matrix is thewater-swellable, erodible, or soluble polymer, which may generally bedescribed as an osmopolymer, hydrogel or water-swellable polymer. Suchpolymers may be linear, branched, or cross linked. The polymers may behomopolymers or copolymers. In certain embodiments, they may besynthetic polymers derived from vinyl, acrylate, methacrylate, urethane,ester and oxide monomers. In other embodiments, they can be derivativesof naturally occurring polymers such as polysaccharides (e.g. chitin,chitosan, dextran and pullulan; gum agar, gum arabic, gum karaya, locustbean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthangum and scleroglucan), starches (e.g. dextrin and maltodextrin),hydrophilic colloids (e.g. pectin), phosphatides (e.g. lecithin),alginates (e.g. ammonium alginate, sodium, potassium or calciumalginate, propylene glycol alginate), gelatin, collagen, andcellulosics. Cellulosics are cellulose polymer that has been modified byreaction of at least a portion of the hydroxyl groups on the sacchariderepeat units with a compound to form an ester-linked or an ether-linkedsubstituent. For example, the cellulosic ethyl cellulose has an etherlinked ethyl substituent attached to the saccharide repeat unit, whilethe cellulosic cellulose acetate has an ester linked acetatesubstituent. In certain embodiments, the cellulosics for the erodiblematrix comprises aqueous-soluble and aqueous-erodible cellulosics caninclude, for example, ethyl cellulose (EC), methylethyl cellulose (MEC),carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC),hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulosepropionate (CP), cellulose butyrate (CB), cellulose acetate butyrate(CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS,hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), andethylhydroxy ethylcellulose (EHEC). In certain embodiments, thecellulosics comprises various grades of low viscosity (MW less than orequal to 50,000 daltons, for example, the Dow Methocel™ series E5,E15LV, E50LV and K100LY) and high viscosity (MW greater than 50,000daltons, for example, E4MCR, E10MCR, K4M, K15M and K100M and theMethocel™ K series) HPMC. Other commercially available types of HPMCinclude the Shin Etsu Metolose 90SH series.

Other materials useful as the erodible matrix material include, but arenot limited to, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol,polyvinyl acetate, glycerol fatty acid esters, polyacrylamide,polyacrylic acid, copolymers of ethacrylic acid or methacrylic acid(EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.) and other acrylic acidderivatives such as homopolymers and copolymers of butylmethacrylate,methylmethacrylate, ethylmethacrylate, ethylacrylate,(2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl)methacrylate chloride.

Alternatively, the agents of the present invention may be administeredby or incorporated into a non-erodible matrix device. In such devices,an agent described herein is distributed in an inert matrix. The agentis released by diffusion through the inert matrix. Examples of materialssuitable for the inert matrix include insoluble plastics (e.g methylacrylate-methyl methacrylate copolymers, polyvinyl chloride,polyethylene), hydrophilic polymers (e.g. ethyl cellulose, celluloseacetate, cross linked polyvinylpyrrolidone (also known ascrospovidone)), and fatty compounds (e.g. carnauba wax, microcrystallinewax, and triglycerides). Such devices are described further inRemington: The Science and Practice of Pharmacy, 20th edition (2000).

As noted above, the agents described herein may also be incorporatedinto an osmotic control device. Such devices generally include a corecontaining one or more agents as described herein and a water permeable,non-dissolving and non-eroding coating surrounding the core whichcontrols the influx of water into the core from an aqueous environmentof use so as to cause drug release by extrusion of some or all of thecore to the environment of use. In certain embodiments, the coating ispolymeric, aqueous-permeable, and has at least one delivery port. Thecore of the osmotic device optionally includes an osmotic agent whichacts to imbibe water from the surrounding environment via such asemi-permeable membrane. The osmotic agent contained in the core of thisdevice may be an aqueous-swellable hydrophilic polymer or it may be anosmogen, also known as an osmagent. Pressure is generated within thedevice which forces the agent(s) out of the device via an orifice (of asize designed to minimize solute diffusion while preventing the build-upof a hydrostatic pressure head). Non limiting examples of osmoticcontrol devices are disclosed in U.S. patent application Ser. No.09/495,061.

The amount of water-swellable hydrophilic polymers present in the coremay range from about 5 to about 80 wt % (including for example, 10 to 50wt %). Non limiting examples of core materials include hydrophilic vinyland acrylic polymers, polysaccharides such as calcium alginate,polyethylene oxide (PEO), polyethylene glycol (PEG), polypropyleneglycol (PPG), poly (2-hydroxyethyl methacrylate), poly (acrylic) acid,poly (methacrylic) acid, polyvinylpyrrolidone (PVP) and cross linkedPVP, polyvinyl alcohol (PVA), PVA/PVP copolymers and PVA/PVP copolymerswith hydrophobic monomers such as methyl methacrylate, vinyl acetate,and the like, hydrophilic polyurethanes containing large PEO blocks,sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC),hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC),carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodiumalginate, polycarbophil, gelatin, xanthan gum, and sodium starchglycolat. Other materials include hydrogels comprising interpenetratingnetworks of polymers that may be formed by addition or by condensationpolymerization, the components of which may comprise hydrophilic andhydrophobic monomers such as those just mentioned. Water-swellablehydrophilic polymers include but are not limited to PEO, PEG, PVP,sodium croscarmellose, HPMC, sodium starch glycolate, polyacrylic acidand cross linked versions or mixtures thereof.

The core may also include an osmogen (or osmagent). The amount ofosmogen present in the core may range from about 2 to about 70 wt %(including, for example, from 10 to 50 wt %). Typical classes ofsuitable osmogens are water-soluble organic acids, salts and sugars thatare capable of imbibing water to thereby effect an osmotic pressuregradient across the barrier of the surrounding coating. Typical usefulosmogens include but are not limited to magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassiumchloride, sodium sulfate, mannitol, xylitol, urea, sorbitol, inositol,raffinose, sucrose, glucose, fructose, lactose, citric acid, succinicacid, tartaric acid, and mixtures thereof. In certain embodiments, theosmogen is glucose, lactose, sucrose, mannitol, xylitol, sodiumchloride, including combinations thereof.

The rate of drug delivery is controlled by such factors as thepermeability and thickness of the coating, the osmotic pressure of thedrug-containing layer, the degree of hydrophilicity of the hydrogellayer, and the surface area of the device. Those skilled in the art willappreciate that increasing the thickness of the coating will reduce therelease rate, while any of the following will increase the release rate:increasing the permeability of the coating; increasing thehydrophilicity of the hydrogel layer; increasing the osmotic pressure ofthe drug-containing layer; or increasing the device's surface area.

In certain embodiments, entrainment of particles of agents describedherein in the extruding fluid during operation of such osmotic device isdesirable. For the particles to be well entrained, the agent drug formis dispersed in the fluid before the particles have an opportunity tosettle in the tablet core. One means of accomplishing this is by addinga disintegrant that serves to break up the compressed core into itsparticulate components. Non limiting examples of standard disintegrantsinclude materials such as sodium starch glycolate (e. g., Explotab™CLV), microcrystalline cellulose (e. g., Avicel™), microcrystallinesilicified cellulose (e. g., ProSoIv™) and croscarmellose sodium (e. g.,Ac-Di-Sol™), and other disintegrants known to those skilled in the art.Depending upon the particular formulation, some disintegrants workbetter than others. Several disintegrants tend to form gels as theyswell with water, thus hindering drug delivery from the device.Non-gelling, non-swelling disintegrants provide a more rapid dispersionof the drug particles within the core as water enters the core. Incertain embodiments, non-gelling, non-swelling disintegrants are resins,for example, ion-exchange resins. In one embodiment, the resin isAmberlite™ IRP 88 (available from Rohm and Haas, Philadelphia, Pa.).When used, the disintegrant is present in amounts ranging from about1-25% of the core agent.

Another example of an osmotic device is an osmotic capsule. The capsuleshell or portion of the capsule shell can be semipermeable. The capsulecan be filled either by a powder or liquid consisting of an agentdescribed herein, excipients that imbibe water to provide osmoticpotential, and/or a water-swellable polymer, or optionally solubilizingexcipients. The capsule core can also be made such that it has a bilayeror multilayer agent analogous to the bilayer, trilayer or concentricgeometries described above.

Another class of osmotic device useful in this invention comprisescoated swellable tablets, for example, as described in EP378404. Coatedswellable tablets comprise a tablet core comprising an agent describedherein and a swelling material, preferably a hydrophilic polymer, coatedwith a membrane, which contains holes, or pores through which, in theaqueous use environment, the hydrophilic polymer can extrude and carryout the agent. Alternatively, the membrane may contain polymeric or lowmolecular weight water-soluble porosigens. Porosigens dissolve in theaqueous use environment, providing pores through which the hydrophilicpolymer and agent may extrude. Examples of porosigens are water-solublepolymers such as HPMC, PEG, and low molecular weight compounds such asglycerol, sucrose, glucose, and sodium chloride. In addition, pores maybe formed in the coating by drilling holes in the coating using a laseror other mechanical means. In this class of osmotic devices, themembrane material may comprise any film-forming polymer, includingpolymers which are water permeable or impermeable, providing that themembrane deposited on the tablet core is porous or containswater-soluble porosigens or possesses a macroscopic hole for wateringress and drug release. Embodiments of this class of sustained releasedevices may also be multilayered, as described, for example, inEP378404.

When an agent described herein is a liquid or oil, such as a lipidvehicle formulation, for example as described in WO05/011634, theosmotic controlled-release device may comprise a soft-gel or gelatincapsule formed with a composite wall and comprising the liquidformulation where the wall comprises a barrier layer formed over theexternal surface of the capsule, an expandable layer formed over thebarrier layer, and a semipermeable layer formed over the expandablelayer. A delivery port connects the liquid formulation with the aqueoususe environment. Such devices are described, for example, in U.S. Pat.Nos. 6,419,952, 6,342,249, 5,324,280, 4,672,850, 4,627,850, 4,203,440,and 3,995,631.

As further noted above, the agents described herein may be provided inthe form of microparticulates, generally ranging in size from about 10μm to about 2 mm (including, for example, from about 100 μm to 1 mm indiameter). Such multiparticulates may be packaged, for example, in acapsule such as a gelatin capsule or a capsule formed from anaqueous-soluble polymer such as HPMCAS, HPMC or starch; dosed as asuspension or slurry in a liquid; or they may be formed into a tablet,caplet, or pill by compression or other processes known in the art. Suchmultiparticulates may be made by any known process, such as wet- anddry-granulation processes, extrusion/spheronization, roller-compaction,melt-congealing, or by spray-coating seed cores. For example, in wet-and dry-granulation processes, the agent described herein and optionalexcipients may be granulated to form multiparticulates of the desiredsize.

The agents can be incorporated into microemulsions, which generally arethermodynamically stable, isotropically clear dispersions of twoimmiscible liquids, such as oil and water, stabilized by an interfacialfilm of surfactant molecules (Encyclopedia of Pharmaceutical Technology,New York: Marcel Dekker, 1992, volume 9). For the preparation ofmicroemulsions, surfactant (emulsifier), co-surfactant (co-emulsifier),an oil phase and a water phase are necessary. Suitable surfactantsinclude any surfactants that are useful in the preparation of emulsions,e.g., emulsifiers that are typically used in the preparation of creams.The co-surfactant (or “co-emulsifier”) is generally selected from thegroup of polyglycerol derivatives, glycerol derivatives and fattyalcohols. Preferred emulsifier/co-emulsifier combinations are generallyalthough not necessarily selected from the group consisting of: glycerylmonostearate and polyoxyethylene stearate; polyethylene glycol andethylene glycol palmitostearate; and caprilic and capric triglyceridesand oleoyl macrogolglycerides. The water phase includes not only waterbut also, typically, buffers, glucose, propylene glycol, polyethyleneglycols, preferably lower molecular weight polyethylene glycols (e.g.,PEG 300 and PEG 400), and/or glycerol, and the like, while the oil phasewill generally comprise, for example, fatty acid esters, modifiedvegetable oils, silicone oils, mixtures of mono- di- and triglycerides,mono- and di-esters of PEG (e.g., oleoyl macrogol glycerides), etc.

The compounds described herein can be incorporated intopharmaceutically-acceptable nanoparticle, nanosphere, and nanocapsuleformulations (Delie and Blanco-Prieto, 2005, Molecule 10:65-80).Nanocapsules can generally entrap compounds in a stable and reproducibleway. To avoid side effects due to intracellular polymeric overloading,ultrafine particles (sized around 0.1 μm) can be designed using polymersable to be degraded in vivo (e.g. biodegradable polyalkyl-cyanoacrylatenanoparticles). Such particles are described in the prior art.

Implantable devices coated with a compound of this invention are anotherembodiment of the present invention. The compounds may also be coated onimplantable medical devices, such as beads, or co-formulated with apolymer or other molecule, to provide a “drug depot”, thus permittingthe drug to be released over a longer time period than administration ofan aqueous solution of the drug. Suitable coatings and the generalpreparation of coated implantable devices are described in U.S. Pat.Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typicallybiocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccharides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

The formulations include those suitable for the administration routesdetailed herein. The formulations may conveniently be presented in unitdosage form and may be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington's. Such methods include the step of bringing into associationthe active ingredient with the carrier which constitutes one or moreaccessory ingredients. In general the formulations are prepared byuniformly and intimately bringing into association the active ingredientwith liquid carriers or finely divided solid carriers or both, and then,if necessary, shaping the product.

The terms “administer”, “administering” or “administration” in referenceto a compound, composition or formulation of the invention meansintroducing the compound into the system of the animal in need oftreatment. When a compound of the invention is provided in combinationwith one or more other active agents, “administration” and its variantsare each understood to include concurrent and/or sequential introductionof the compound and the other active agents.

The compositions described herein may be administered systemically orlocally, e.g.: orally (e.g. using capsules, powders, solutions,suspensions, tablets, sublingual tablets and the like), by inhalation(e.g. with an aerosol, gas, inhaler, nebulizer or the like), to the ear(e.g. using ear drops), topically (e.g. using creams, gels, liniments,lotions, ointments, pastes, transdermal patches, etc), ophthalmically(e.g. with eye drops, ophthalmic gels, ophthalmic ointments), rectally(e.g. using enemas or suppositories), nasally, buccally, vaginally (e.g.using douches, intrauterine devices, vaginal suppositories, vaginalrings or tablets, etc), via an implanted reservoir or the like, orparenterally depending on the severity and type of the disease beingtreated. The term “parenteral” as used herein includes, but is notlimited to, subcutaneous, intravenous, intramuscular, intra-articular,intra-synovial, intrasternal, intrathecal, intrahepatic, intralesionaland intracranial injection or infusion techniques. Preferably, thecompositions are administered orally, intraperitoneally orintravenously.

The pharmaceutical compositions described herein may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. Liquiddosage forms for oral administration include, but are not limited to,pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. Tablets may be uncoated or may be coated by knowntechniques including microencapsulation to mask an unpleasant taste orto delay disintegration and adsorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed. A water soluble taste maskingmaterial such as hydroxypropyl-methylcellulose orhydroxypropyl-cellulose may be employed.

Formulations of a compound of Formula I and Formula I′ that are suitablefor oral administration may be prepared as discrete units such astablets, pills, troches, lozenges, aqueous or oil suspensions,dispersible powders or granules, emulsions, hard or soft capsules, e.g.gelatin capsules, syrups or elixirs. Formulations of a compound intendedfor oral use may be prepared according to any method known to the artfor the manufacture of pharmaceutical compositions.

Compressed tablets may be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above.

When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening and/or flavoring agents may be added. Syrupsand elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

Sterile injectable forms of the compositions described herein (e.g. forparenteral administration) may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose, any bland fixed oil may be employedincluding synthetic mono- or di-glycerides. Fatty acids, such as oleicacid and its glyceride derivatives are useful in the preparation ofinjectables, as are natural pharmaceutically-acceptable oils, such asolive oil or castor oil, especially in their polyoxyethylated versions.These oil solutions or suspensions may also contain a long-chain alcoholdiluent or dispersant, such as carboxymethyl cellulose or similardispersing agents which are commonly used in the formulation ofpharmaceutically acceptable dosage forms including emulsions andsuspensions. Other commonly used surfactants, such as Tweens, Spans andother emulsifying agents or bioavailability enhancers which are commonlyused in the manufacture of pharmaceutically acceptable solid, liquid, orother dosage forms may also be used for the purposes of injectableformulations.

Oily suspensions may be formulated by suspending a compound of Formula Iand Formula I′ in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in mineral oil such as liquid paraffin.The oily suspensions may contain a thickening agent, for examplebeeswax, hard paraffin or cetyl alcohol. Sweetening agents such as thoseset forth above, and flavoring agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as butylated hydroxyanisol oralpha-tocopherol.

Aqueous suspensions of a compound of Formula I and Formula I′ containthe active materials in admixture with excipients suitable for themanufacture of aqueous suspensions. Such excipients include a suspendingagent, such as sodium carboxymethylcellulose, croscarmellose, povidone,methylcellulose, hydroxypropyl methylcelluose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing orwetting agents such as a naturally occurring phosphatide (e.g.,lecithin), a condensation product of an alkylene oxide with a fatty acid(e.g., polyoxyethylene stearate), a condensation product of ethyleneoxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound described herein, it isoften desirable to slow the absorption of the compound from subcutaneousor intramuscular injection. This may be accomplished by the use of aliquid suspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsulated matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

The injectable solutions or microemulsions may be introduced into apatient's bloodstream by local bolus injection. Alternatively, it may beadvantageous to administer the solution or microemulsion in such a wayas to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized. An example ofsuch a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds describedherein with suitable non-irritating excipients or carriers such as cocoabutter, beeswax, polyethylene glycol or a suppository wax which aresolid at ambient temperature but liquid at body temperature andtherefore melt in the rectum or vaginal cavity and release the activecompound. Other formulations suitable for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprays.

The pharmaceutical compositions described herein may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the ear, the skin, or the lower intestinal tract.Suitable topical formulations are readily prepared for each of theseareas or organs.

Dosage forms for topical or transdermal administration of a compounddescribed herein include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel. Topical applicationfor the lower intestinal tract can be effected in a rectal suppositoryformulation (see above) or in a suitable enema formulation.Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum. For treatment of theeye or other external tissues, e.g., mouth and skin, the formulationsmay be applied as a topical ointment or cream containing the activeingredient(s) in an amount of, for example, 0.075 to 20% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither an oil-based, paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream withan oil-in-water cream base. If desired, the aqueous phase of the creambase may include a polyhydric alcohol, i.e. an alcohol having two ormore hydroxyl groups such as propylene glycol, butane 1,3-diol,mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400)and mixtures thereof. The topical formulations may desirably include acompound which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include dimethyl sulfoxide and relatedanalogs.

The oily phase of emulsions prepared using a compound of Formula I andFormula I′ may be constituted from known ingredients in a known manner.While the phase may comprise merely an emulsifier (otherwise known as anemulgent), it desirably comprises a mixture of at least one emulsifierwith a fat or an oil or with both a fat and an oil. A hydrophilicemulsifier may be included together with a lipophilic emulsifier whichacts as a stabilizer. In some embodiments, the emulsifier includes bothan oil and a fat. Together, the emulsifier(s) with or withoutstabilizer(s) make up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulgents and emulsion stabilizers suitable for use in the formulationof a compound of Formula I and Formula I′ include Tween™-60, Span™-80,cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glycerylmono-stearate and sodium lauryl sulfate.

The pharmaceutical compositions may also be administered by nasalaerosol or by inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other conventional solubilizing or dispersingagents. Formulations suitable for intrapulmonary or nasal administrationhave a particle size for example in the range of 0.1 to 500 micros(including particles in a range between 0.1 and 500 microns inincrements microns such as 0.5, 1, 30, 35 microns, etc) which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs.

The pharmaceutical composition (or formulation) for use may be packagedin a variety of ways depending upon the method used for administeringthe drug. Generally, an article for distribution includes a containerhaving deposited therein the pharmaceutical formulation in anappropriate form. Suitable containers are well-known to those skilled inthe art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

The formulations may be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

In another aspect, a compound of Formula I and Formula I′ or apharmaceutically acceptable salt thereof may be formulated in aveterinary composition comprising a veterinary carrier. Veterinarycarriers are materials useful for the purpose of administering thecomposition and may be solid, liquid or gaseous materials which areotherwise inert or accepFormula I and Formula I′n the veterinary art andare compatible with the active ingredient. These veterinary compositionsmay be administered parenterally, orally or by any other desired route.

Therapeutic Methods

In a third aspect, the invention relates to the treatment of certaindisorders by using sGC stimulators, either alone or in combination, ortheir pharmaceutically acceptable salts or pharmaceutical compositionscomprising them, in a patient in need thereof.

The present disclosure relates to stimulators of soluble guanylatecyclase (sGC), pharmaceutical formulations thereof and their use, aloneor in combination with one or more additional agents, for treatingand/or preventing various diseases, wherein an increase in theconcentration of NO or an increase in the concentration of cGMP might bedesirable. The diseases that can be treated include but are not limitedto pulmonary hypertension, arterial hypertension, heart failure,atherosclerosis, inflammation, thrombosis, renal fibrosis and failure,liver cirrhosis, erectile dysfunction, female sexual disorders,disorders related to diabetes, ocular disorders and other relatedcardiovascular disorders.

Increased concentration of cGMP leads to vasodilation, inhibition ofplatelet aggregation and adhesion, anti-hypertensive effects,anti-remodeling effects, anti-apoptotic effects, anti-inflammatoryeffects and neuronal signal transmission effects. Thus, sGC stimulatorsmay be used to treat and/or prevent a range of diseases and disorders,including but not limited to a peripheral, pulmonary, hepatic, liver,cardiac or cerebral vascular/endothelial disorders or conditions, aurogenital-gynecological or sexual disorder or condition, athromboembolic disease, an ischemic disease, a fibrotic disorder, atopical or skin disorder, a pulmonary or respiratory disorder, a renalor hepatic disorder, a metabolic disorder, atherosclerosis, or a lipidrelated disorder.

In other embodiments, the compounds here disclosed are sGC stimulatorsthat may be useful in the prevention and/or treatment of diseases anddisorders characterized by undesirable reduced bioavailability of and/orsensitivity to NO, such as those associated with conditions of oxidativestress or nitrosative stress.

Throughout this disclosure, the terms “hypertension”, “arterialhypertension” or “high blood pressure (HBP)” are used interchangeableand refer to an extremely common and highly preventable chroniccondition in which blood pressure (BP) in the arteries is higher thannormal. If not properly controlled, it represents a significant riskfactor for several serious cardiovascular and renal conditions.Hypertension may be a primary disease, called “essential hypertension”or “idiopathic hypertension”, or it may be caused by other diseases, inwhich case it is classified as “secondary hypertension”. Essentialhypertension accounts for 90-95% of all cases.

As used herein, the term “resistant hypertension” refers to hypertensionthat remains above goal blood pressure (usually less than 140/90 mmHg,although a lower goal of less than 130/80 mmHg is recommended forpatients with comorbid diabetes or kidney disease), in spite ofconcurrent use of three antihypertensive agents belonging to differentantihypertensive drug classes. People who require four or more drugs tocontrol their blood pressure are also considered to have resistanthypertension. Hypertension is an extremely common comorbid condition indiabetes, affecting ˜20-60% of patients with diabetes, depending onobesity, ethnicity, and age. This type of hypertension is hereinreferred to as “diabetic hypertension”. In type 2 diabetes, hypertensionis often present as part of the metabolic syndrome of insulin resistancealso including central obesity and dyslipidemia. In type 1 diabetes,hypertension may reflect the onset of diabetic nephropathy.

“Pulmonary hypertension (PH)”, as used herein, is a diseasecharacterized by sustained elevations of blood pressure in the pulmonaryvasculature (pulmonary artery, pulmonary vein and pulmonarycapillaries), which results in right heart hypertrophy, eventuallyleading to right heart failure and death. Common symptoms of PH includeshortness of breath, dizziness and fainting, all of which areexacerbated by exertion. Without treatment, median life expectancyfollowing diagnosis is 2.8 years. PH exists in many different forms,which are categorized according to their etiology. Categories includepulmonary arterial hypertension (PAH), PH with left heart disease, PHassociated with lung diseases and/or hypoxaemia, PH due to chronicthrombotic and/or embolic disease and miscellaneous PH. PAH is rare inthe general population, but the prevalence increases in association withcertain common conditions such as HIV infection, scleroderma and sicklecell disease. Other forms of PH are generally more common than PAH, and,for instance, the association of PH with chronic obstructive pulmonarydisease (COPD) is of particular concern. Current treatment for pulmonaryhypertension depends on the stage and the mechanism of the disease.

As used herein “heart failure” is a progressive disorder of leftventricular (LV) myocardial remodeling that culminates in a complexclinical syndrome in which impaired cardiac function and circulatorycongestion are the defining features, and results in insufficientdelivery of blood and nutrients to body tissues. The condition occurswhen the heart is damaged or overworked and unable to pump out all theblood that returns to it from the systemic circulation. As less blood ispumped out, blood returning to the heart backs up and fluid builds up inother parts of the body. Heart failure also impairs the kidneys' abilityto dispose of sodium and water, complicating fluid retention further.Heart failure is characterized by autonomic dysfunction, neurohormonalactivation and overproduction of cytokines, which contribute toprogressive circulatory failure. Symptoms of heart failure include:dyspnea (shortness of breath) while exercising or resting and waking atnight due to sudden breathlessness, both indicative of pulmonary edema;general fatigue or weakness, edema of the feet, ankles and legs, rapidweight gain, chronic cough, including that producing mucus or blood.Depending on its clinical presentation, heart failure is classified asde novo, transient or chronic. Acute heart failure, i.e. the rapid orgradual onset of symptoms requiring urgent therapy, may develop de novoor as a result of chronic heart failure becoming decompensated. Diabetesis a common comorbidity in patients with heart failure and is associatedwith poorer outcomes as well as potentially compromising the efficacy oftreatments. Other important comorbidities include systemic hypertension,chronic airflow obstruction, sleep apnea, cognitive dysfunction, anemia,chronic kidney disease and arthritis. Chronic left heart failure isfrequently associated with the development of pulmonary hypertension.The frequency of certain comorbidities varies by gender: among women,hypertension and thyroid disease are more common, while men morecommonly suffer from chronic obstructive pulmonary disease (COPD),peripheral vascular disease, coronary artery disease and renalinsufficiency. Depression is a frequent comorbidity of heart failure andthe two conditions can and often do complicate one another. Cachexia haslong been recognized as a serious and frequent complication of heartfailure, affecting up to 15% of all heart failure patients and beingassociated with poor prognosis. Cardiac cachexia is defined as thenonedematous, nonvoluntary loss of at least 6% of body weight over aperiod of six months.

The term “sleep apnea” refers to the most common of the sleep-disorderedbreathing disorders. It is a condition characterized by intermittent,cyclical reductions or total cessations of airflow, which may or may notinvolve obstruction of the upper airway. There are three types of sleepapnea: obstructive sleep apnea, the most common form, central sleepapnea and mixed sleep apnea.

“Central sleep apnea (CSA)”, is caused by a malfunction in the brain'snormal signal to breathe, rather than physical blockage of the airway.The lack of respiratory effort leads to an increase in carbon dioxide inthe blood, which may rouse the patient. CSA is rare in the generalpopulation, but is a relatively common occurrence in patients withsystolic heart failure.

As used herein, the term “metabolic syndrome”, “insulin resistancesyndrome” or “syndrome X”, refers to a group or clustering of metabolicconditions (abdominal obesity, elevated fasting glucose, “dyslipidemia”(i.e., elevated lipid levels) and elevated blood pressure (HBP)) whichoccur together more often than by chance alone and that together promotethe development of type 2 diabetes and cardiovascular disease. Metabolicsyndrome is characterized by a specific lipid profile of increasedtriglycerides, decreased high-density lipoprotein cholesterol(HDL-cholesterol) and in some cases moderately elevated low-densitylipoprotein cholesterol (LDL-cholesterol) levels, as well as acceleratedprogression of “atherosclerotic disease” due to the pressure of thecomponent risk factors. There are several types of dyslipidemias:“hypercholesterolemia” refers to elevated levels of cholesterol.Familial hypercholesterolemia is a specific form of hypercholesterolemiadue to a defect on chromosome 19 (19p13.1-13.3). “Hyperglyceridemia”refers to elevated levels of glycerides (e.g., “hypertrigliceridemia”involves elevated levels of triglycerides). “Hyperlipoproteinemia”refers to elevated levels of lipoproteins (usually LDL unless otherwisespecified).

As used herein, the term “peripheral vascular disease (PVD)”, alsocommonly referred to as “peripheral arterial disease (PAD)” or“peripheral artery occlusive disease (PAOD)”, refers to the obstructionof large arteries not within the coronary, aortic arch vasculature, orbrain. PVD can result from atherosclerosis, inflammatory processesleading to stenosis, an embolism, or thrombus formation. It causeseither acute or chronic “ischemia (lack of blood supply)”. Often PVD isa term used to refer to atherosclerotic blockages found in the lowerextremity. PVD also includes a subset of diseases classified asmicrovascular diseases resulting from episodal narrowing of the arteries(e.g., “Raynaud's phenomenon”), or widening thereof (erythromelalgia),i.e. vascular spasms.

The term “thrombosis” refers to the formation of a blood clot(“thrombus”) inside a blood vessel, obstructing the flow of bloodthrough the circulatory system. When a blood vessel is injured, the bodyuses platelets (thrombocytes) and fibrin to form a blood clot to preventblood loss. Alternatively, even when a blood vessel is not injured,blood clots may form in the body if the proper conditions presentthemselves. If the clotting is too severe and the clot breaks free, thetraveling clot is now known as an “embolus”. The term “thromboembolism”refers to the combination of thrombosis and its main complication,“embolism”. When a thrombus occupies more than 75% of surface area ofthe lumen of an artery, blood flow to the tissue supplied is reducedenough to cause symptoms because of decreased oxygen (hypoxia) andaccumulation of metabolic products like lactic acid (“gout”). More than90% obstruction can result in anoxia, the complete deprivation ofoxygen, and “infarction”, a mode of cell death.

An “embolism” (plural embolisms) is the event of lodging of an embolus(a detached intravascular mass capable of clogging arterial capillarybeds at a site far from its origin) into a narrow capillary vessel of anarterial bed which causes a blockage (vascular occlusion) in a distantpart of the body. This is not to be confused with a thrombus whichblocks at the site of origin.

A “stroke”, or cerebrovascular accident (CVA), is the rapid loss ofbrain function(s) due to disturbance in the blood supply to the brain.This can be due to “ischemia” (lack of blood flow) caused by blockage(thrombosis, arterial embolism), or a hemorrhage (leakage of blood). Asa result, the affected area of the brain cannot function, which mightresult in an inability to move one or more limbs on one side of thebody, inability to understand or formulate speech, or an inability tosee one side of the visual field. Risk factors for stroke include oldage, hypertension, previous stroke or transient ischemic attack (TIA),diabetes, high cholesterol, cigarette smoking and atrial fibrillation.High blood pressure is the most important modifiable risk factor ofstroke. An “ischemic stroke” is occasionally treated in a hospital withthrombolysis (also known as a “clot buster”), and some hemorrhagicstrokes benefit from neurosurgery. Prevention of recurrence may involvethe administration of antiplatelet drugs such as aspirin anddipyridamole, control and reduction of hypertension, and the use ofstatins. Selected patients may benefit from carotid endarterectomy andthe use of anticoagulants.

“Ischemia” is a restriction in blood supply to tissues, causing ashortage of oxygen and glucose needed for cellular metabolism (to keeptissue alive). Ischemia is generally caused by problems with bloodvessels, with resultant damage to or dysfunction of tissue. It alsomeans local anemia in a given part of a body sometimes resulting fromcongestion (such as vasoconstriction, thrombosis or embolism).

According to the American Psychiatric Association's Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition (DSM-IV), theterm “sexual dysfunction” encompasses a series of conditions“characterized by disturbances in sexual desire and in thepsychophysiological changes associated with the sexual response cycle”;while problems of this type are common, sexual dysfunction is onlyconsidered to exist when the problems cause distress for the patient.Sexual dysfunction can be either physical or psychological in origin. Itcan exist as a primary condition, generally hormonal in nature, althoughmost often it is secondary to other medical conditions or to drugtherapy for said conditions. All types of sexual dysfunction can befurther classified as life-long, acquired, situational or generalized(or combinations thereof).

The DSM-IV-TR specifies five major categories of “female sexualdysfunction”: sexual desire/interest disorders; “sexual arousaldisorders (including genital, subjective and combined)”; orgasmicdisorder; dyspareunia and vaginismus; and persistent sexual arousaldisorder.

“Female sexual arousal disorder (FSAD)” is defined as a persistent orrecurring inability to attain or maintain sufficient levels of sexualexcitement, causing personal distress. FSAD encompasses both the lack ofsubjective feelings of excitement (i.e., subjective sexual arousaldisorder) and the lack of somatic responses such as lubrication andswelling (i.e., genital/physical sexual arousal disorder). FSAD may bestrictly psychological in origin, although it generally is caused orcomplicated by medical or physiological factors. Hypoestrogenism is themost common physiologic condition associated with FSAD, which leads tourogenital atrophy and a decrease in vaginal lubrication.

As used herein, “erectile dysfunction (ED)” is a male sexual dysfunctioncharacterized by the inability to develop or maintain an erection of thepenis during sexual performance. A penile erection is the hydrauliceffect of blood entering and being retained in sponge-like bodies withinthe penis. The process is often initiated as a result of sexual arousal,when signals are transmitted from the brain to nerves in the penis.Erectile dysfunction is indicated when an erection is difficult toproduce. The most important organic causes are cardiovascular diseaseand diabetes, neurological problems (for example, trauma fromprostatectomy surgery), hormonal insufficiencies (hypogonadism) and drugside effects.

As used herein, the term “bronchoconstriction” is used to define theconstriction of the airways in the lungs due to the tightening ofsurrounding smooth muscle, with consequent coughing, wheezing, andshortness of breath. The condition has a number of causes, the mostcommon being as well as asthma. Exercise and allergies can bring on thesymptoms in an otherwise asymptomatic individual. Other conditions suchas chronic obstructive pulmonary disease (COPD) can also present withbronchoconstriction.

Specific diseases of disorders which may be treated and/or prevented byadministering an sGC stimulator of the invention, include but are notlimited to: hypertension (e.g., diabetic hypertension, arterialhypertension, pulmonary hypertension, resistant hypertension, peripheralartery disease, etc), heart failure (e.g., left ventricular diastolicdysfunction (LVDD) and left ventricular systolic dysfunction (LVSD),sleep apnea associated with heart failure), arteriosclerotic disease(e.g., atherosclerosis), thromboembolic disorders (e.g., chronicthromboembolic pulmonary hypertension, thrombosis, stroke, embolism,pulmonary embolism), Alzheimer's disease, renal diseases (e.g., renalfibrosis, ischemic renal disease, renal failure, renal insufficiency,chronic kidney disease), hepatic disease (e.g., liver fibrosis orcirrhosis), respiratory disease (e.g., pulmonary fibrosis, asthma,chronic obstructive pulmonary disease, interstitial lung disease),sexual disorders (e.g., erectile dysfunction, male and female sexualdysfunction, vaginal atrophy), sickle cell anemia, neuro inflammatorydiseases or disorders and metabolic disorders (e.g., lipid relateddisorders).

The compounds of Formula I and Formula I′ as well as pharmaceuticallyacceptable salts thereof, as stimulators of sGC, are useful in theprevention and/or treatment of the following types of diseases,conditions and disorders which can benefit from sGC stimulation:

(1) Peripheral, pulmonary, hepatic, kidney, cardiac or cerebralvascular/endothelial disorders/conditions or diseases otherwise relatedto circulation:

disorders related to high blood pressure and decreased coronary bloodflow such as increased acute and chronic coronary blood pressure,arterial hypertension and vascular disorder resulting from cardiac andrenal complications (e.g. heart disease, stroke, cerebral ischemia,renal failure); resistant hypertension, diabetic hypertension,congestive heart failure; diastolic or systolic dysfunction; coronaryinsufficiency; arrhythmias; reduction of ventricular preload; cardiachypertrophy; heart failure/cardiorenal syndrome; portal hypertension;endothelial dysfunction or injury;

thromboembolic disorders and ischemias such as myocardial infarction,stroke, transient ischemic attacks (TIAs); obstructive thromboanginitis;stable or unstable angina pectoris; coronary spasms, variant angina,Prinzmetal's angina; prevention of restenosis after thrombolysistherapies; thrombogenic disoders;

Alzheimer's disease; Parkinson's disease; dementia; vascular cognitiveimpairment; cerebral vasospasm; traumatic brain injury;

peripheral arterial disease, peripheral occlusive arterial disease;peripheral vascular disease; hypertonia; Raynaud's syndrome orphenomenon, critical limb ischemia, vasculitis; peripheral embolism;intermittent claudication; vaso-occlusive crisis; Duchene's and Beckermuscular dystrophies; microcirculation abnormalities; control ofvascular leakage or permeability;

shock; sepsis; cardiogenic shock; control of leukocyte activation;inhibition or modulation of platelet aggregation;

pulmonary/respiratory conditions such as pulmonary hypertension,pulmonary arterial hypertension, and associated pulmonary vascularremodeling (e.g. localized thrombosis and right heart hypertrophy);pulmonary hypertonia; primary pulmonary hypertension, secondarypulmonary hypertension, familial pulmonary hypertension, sporadicpulmonary hypertension, pre-capillary pulmonary hypertension, idiopathicpulmonary hypertension, thrombotic pulmonary arteriopathy, plexogenicpulmonary arteriopathy; cystic fibrosis; bronchoconstriction orpulmonary bronchoconstriction; acute respiratory distress syndrome; lungfibrosis, lung transplant;

pulmonary hypertension associated with or related to: left ventriculardysfunction, hypoxemia, WHO groups I, II, III, IV and V hypertensions,mitral valve disease, constrictive pericarditis, aortic stenosis,cardiomyopathy, mediastinal fibrosis, pulmonary fibrosis, anomalouspulmonary venous drainage, pulmonary venooclusive disease, pulmonaryvasculitis, collagen vascular disease, congenital heart disease,pulmonary venous hypertension, interstitial lung disease,sleep-disordered breathing, sleep apnea, alveolar hypoventilationdisorders, chronic exposure to high altitude, neonatal lung disease,alveolar-capillary dysplasia, sickle cell disease, other coagulationdisorders, chronic thromboembolism, pulmonary embolism (due to tumor,parasites or foreign material), connective tissue disease, lupus,schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease,asthma, emphysema, chronic bronchitis, pulmonary capillaryhemangiomatosis; histiocytosis X, lymphangiomatosis and compressedpulmonary vessels (such as due to adenopathy, tumor or fibrosingmediastinitis);

arterosclerotic diseases or conditions such as atherosclerosis (e.g.,associated with endothelial injury, platelet and monocyte adhesion andaggregation, smooth muscle proliferation and migration); restenosis(e.g. developed after thrombolysis therapies, percutaneous transluminalangioplasties (PTAs), percutaneous transluminal coronary angioplasties(PTCAs) and bypass); inflammation;

cardiovascular disease associated with metabolic syndrome (e.g.,obesity, dyslipidemia, diabetes, high blood pressure); lipid relateddisorders such as dyslipidemia, hypercholesterolemia,hypertriglyceridemia, sitosterolemia, fatty liver disease, andhepatitis; preeclamsia; polycystic kidney disease progression;subcutaneous fat; obesity;

liver cirrhosis, associated with chronic liver disease, hepaticfibrosis, hepatic stellate cell activation, hepatic fibrous collagen andtotal collagen accumulation; liver disease of necro-inflammatory and/orof immunological origin; and urogenital system disorders, such as renalfibrosis and renal failure resulting from chronic kidney diseases orinsufficiency (e.g. due to accumulation/deposition and tissue injury,progressive sclerosis, glomerulonephritis); prostate hypertrophysystemic sclerosis; cardiac interstitial fibrosis; cardiac remodelingand fibrosis; cardiac hypertrophy;

(2) ischemia, reperfussion damage; ischemia/reperfussion associated withorgan transplant, lung transplant, pulmonary transplant, cardiactransplant; conserving blood substituents in trauma patients;(3) sexual, gynecologicaland urological disorders of conditions:erectile dysfunction; impotence; premature ejaculation; female sexualdysfunction (e.g., female sexual arousal dysfunction, hypoactive sexualarousal disorder), vaginal atrophy, dyspaneuria, atrophic vaginitis;benign prostatic hyperplasia (BPH) or hypertrophy or enlargement,bladder outlet obstruction; bladder pain syndrome (BPS), interstitialcystitis (IC), overactive bladder, neurogenic bladder and incontinence;diabetic nephropathy;(4) ocular diseases or disorders: glaucoma, retinopathy, diabeticretinopathy, blepharitis, dry eye syndrome, Sjögren's Syndrome;(5) hearing diseases or disorders: hearing impairment, partial or totalhearing loss; partial or total deafness; tinnitus; noise-induced hearingloss;(6) topical or skin disorders or conditions: dermal fibrosis,scleroderma, skin fibrosis;(7) wound healing: for instance in diabetics; microvascular perfusionimprovement (e.g., following injury, to counteract the inflammatoryresponse in perioperative care), anal fissures, diabetic ulcers; and(8) other diseases or conditions: cancer metastasis, osteoporosis,gastroparesis; functional dyspepsia; diabetic complications, diseasesassociated with endothelial dysfunction, and neurologic disordersassociated with decreased nitric oxide production.

In other embodiments of the invention, the compounds of Formula I andFormula I′ as well as pharmaceutically acceptable salts thereof areuseful in the prevention and/or treatment of the following types ofdiseases, conditions and disorders which can benefit from sGCstimulation:

hypertension, resistant hypertension, diabetic hypertension, pulmonaryhypertension (PH), pulmonary arterial hypertension, PH associated withCOPD, chronic airflow obstruction, asthma or pulmonary fibrosis,thrombosis, embolism, thromboembolic disorders, Alzheimer's disease,atherosclerosis, right heart hypertrophy, heart failure, diastolicdysfunction, systolic dysfunction, sleep apnea associated with heartfailure, liver cirrhosis, renal fibrosis, renal failure resulting fromchronic kidney diseases or insufficiency, metabolic disorder,dyslipidemia, hypercholesterolemia, hypertriglyceridemia,sitosterolemia, fatty liver disease, hepatitis, erectile dysfunction,female sexual dysfunction, female sexual arousal dysfunction and vaginalatrophy.

In some embodiments, the invention relates to a method of treating adisease, health condition or disorder in a subject, comprisingadministering a therapeutically effective amount of a compound of any ofthe above depicted Formulae, or a pharmaceutically acceptable saltthereof, to the subject in need of treatment, wherein the disease,health condition or disorder is selected from one of the diseases listedabove.

In other embodiments the disease, health condition or disorder isselected from a peripheral, pulmonary, hepatic, kidney, cardiac orcerebral vascular/endothelial disorder or condition, or a diseaseotherwise related to circulation selected from: increased acute andchronic coronary blood pressure, arterial hypertension and vasculardisorder resulting from cardiac and renal complications, heart disease,stroke, cerebral ischemia, renal failure; resistant hypertension,diabetic hypertension, congestive heart failure; diastolic or systolicdysfunction; coronary insufficiency; arrhythmias; reduction ofventricular preload; cardiac hypertrophy; heart failure/cardiorenalsyndrome; portal hypertension; endothelial dysfunction or injury;myocardial infarction; stroke or transient ischemic attacks (TIAs);obstructive thromboanginitis; stable or unstable angina pectoris;coronary spasms, variant angina, Prinzmetal's angina; restenosis as aresult of thrombolysis therapies and thrombogenic disoders.

In still other embodiments, the disease, health condition or disorder isselected from a peripheral vascular/endothelial disorder or condition ora disease otherwise related to circulation selected from: peripheralarterial disease, peripheral occlusive arterial disease; peripheralvascular disease; hypertonias; Raynaud's syndrome or phenomenon;critical limb ischemia; vasculitis; peripheral embolism; intermittentclaudication; vaso-occlusive crisis; Duchene's and Becker musculardystrophies; microcirculation abnormalities; and vascular leakage orpermeability issues.

In further embodiments, the disease, health condition or disorder is apulmonary disorder or condition or a disease otherwise related tocirculation selected from: pulmonary hypertension; pulmonary arterialhypertension and associated pulmonary vascular remodeling; localizedthrombosis; right heart hypertrophy; pulmonary hypertonia; primarypulmonary hypertension, secondary pulmonary hypertension, familialpulmonary hypertension, sporadic pulmonary hypertension, pre-capillarypulmonary hypertension, idiopathic pulmonary hypertension, thromboticpulmonary arteriopathy, plexogenic pulmonary arteriopathy; cysticfibrosis; bronchoconstriction or pulmonary bronchoconstriction; acuterespiratory distress syndrome; lung fibrosis and lung transplant. Insome of these embodiments, the pulmonary hypertension is pulmonaryhypertension associated with or related to: left ventriculardysfunction, hypoxemia, WHO groups I, II, III, IV and V hypertensions,mitral valve disease, constrictive pericarditis, aortic stenosis,cardiomyopathy, mediastinal fibrosis, pulmonary fibrosis, anomalouspulmonary venous drainage, pulmonary venooclusive disease, pulmonaryvasculitis, collagen vascular disease, congenital heart disease,pulmonary venous hypertension, interstitial lung disease,sleep-disordered breathing, sleep apnea, alveolar hypoventilationdisorders, chronic exposure to high altitude, neonatal lung disease,alveolar-capillary dysplasia, sickle cell disease, coagulationdisorders, chronic thromboembolism; pulmonary embolism, due to tumor,parasites or foreign material; connective tissue disease, lupus,schistosomiasis, sarcoidosis, chronic obstructive pulmonary disease,asthma, emphysema, chronic bronchitis, pulmonary capillaryhemangiomatosis; histiocytosis X; lymphangiomatosis and compressedpulmonary vessels due to adenopathy, tumor or fibrosing mediastinitis.

In still other embodiments, the health condition or disorder is avascular or endothelial disorder or condition or a disease otherwiserelated to circulation selected from: arterosclerotic diseases;atherosclerosis, atherosclerosis associated with endothelial injury,atherosclerosis associated with platelet and monocyte adhesion andaggregation, atherosclerosis associated with smooth muscle proliferationand migration; restenosis, restenosis developed after thrombolysistherapies; restenosis developed after percutaneous transluminalangioplasties; restensosis developed after percutaneous transluminalcoronary angioplasties and bypass; inflammation; cardiovascular diseaseassociated with metabolic syndrome, obesity, dyslipidemia, diabetes orhigh blood pressure; lipid related disorders, dyslipidemia,hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liverdisease, and hepatitis; preeclamsia; polycystic kidney diseaseprogression; and subcutaneous fat.

In yet other embodiments, the disease, health condition or disorderselected from liver cirrhosis, liver cirrhosis associated with chronicliver disease, hepatic fibrosis, hepatic stellate cell activation,hepatic fibrous collagen and total collagen accumulation; and liverdisease of necro-inflammatory or of immunological origin.

In further embodiments, the disease, health condition or disorder is aurogenital system disorder selected from renal fibrosis; renal failureresulting from chronic kidney diseases or insufficiency; renal failuredue to accumulation or deposition and tissue injury, progressivesclerosis or glomerulonephritis; and prostatic hypertrophy.

In further embodiments, the disease, health condition or disorder issystemic sclerosis.

In further embodiments, the disease, health condition or disorder is acardiac disorder selected from cardiac interstitial fibrosis; cardiacremodeling and fibrosis and cardiac hypertrophy.

In further embodiments, the disease, health condition or disorder is aCNS disorder or condition selected from Alzheimer's disease; Parkinson'sdisease; dementia; vascular cognitive impairment; cerebral vasospasm;and traumatic brain injury.

In further embodiments, the disease, health condition or disorder isselected from ischemia, reperfussion damage; ischemia/reperfussionassociated with organ transplant, lung transplant, pulmonary transplantor cardiac transplant; conserving blood substituents in trauma patients.

In further embodiments, the disease, health condition or disorder is asexual, gynecological or urological disorder of condition selected fromerectile dysfunction; impotence; premature ejaculation; female sexualdysfunction; female sexual arousal dysfunction; hypoactive sexualarousal disorder; vaginal atrophy, dyspaneuria, atrophic vaginitis;benign prostatic hyperplasia (BPH) or hypertrophy or enlargement;bladder outlet obstruction; bladder pain syndrome (BPS); interstitialcystitis (IC); overactive bladder, neurogenic bladder and incontinence;diabetic nephropathy.

In further embodiments, the disease, health condition or disorder isselected from vaginal atrophy, dyspaneuria and atrophic vaginitis.

In further embodiments, the disease, health condition or disorder isselected from benign prostatic hyperplasia (BPH) or hypertrophy orenlargement; bladder outlet obstruction; bladder pain syndrome (BPS);interstitial cystitis (IC); overactive bladder, neurogenic bladder andincontinence.

In further embodiments, the disease, health condition or disorder is asexual, condition selected from erectile dysfunction; impotence;premature ejaculation; female sexual dysfunction; female sexual arousaldysfunction and hypoactive sexual arousal disorder.

In further embodiments, the disease or disorder is diabetic nephropathy.

In further embodiments, the disease, health condition or disorder isDuchene's and Becker muscular dystrophies.

In further embodiments, the disease is an ocular diseases or disorderselected from glaucoma, retinopathy, diabetic retinopathy, blepharitis,dry eye syndrome and Sjögren's Syndrome.

In further embodiments, the disease is a hearing diseases or disorderselected from hearing impairment, partial or total hearing loss; partialor total deafness; tinnitus; and noise-induced hearing loss.

In further embodiments, the disease is a topical or skin disorders orcondition selected from dermal fibrosis, scleroderma and skin fibrosis.

In further embodiments, the treatment involves wound healing; woundhealing in diabetics; improvement of microvascular perfusion;improvement of microvascular perfusion issues following injury;treatment of anal fissures; and treatment of diabetic ulcers.

In further embodiments, the disease or condition is selected from cancermetastasis; osteoporosis; gastroparesis; functional dyspepsia; diabeticcomplications; diseases associated with endothelial dysfunction andneurologic disorders associated with decreased nitric oxide production.

In another embodiment, compounds of the invention can be delivered inthe form of implanted devices, such as stents. A stent is a mesh ‘tube’inserted into a natural passage/conduit in the body to prevent orcounteract a disease-induced, localized flow constriction. The term mayalso refer to a tube used to temporarily hold such a natural conduitopen to allow access for surgery.

A drug-eluting stent (DES) is a peripheral or coronary stent (ascaffold) placed into narrowed, diseased peripheral or coronary arteriesthat slowly releases a drug to block cell proliferation, usually smoothmuscle cell proliferation. This prevents fibrosis that, together withclots (thrombus), could otherwise block the stented artery, a processcalled restenosis. The stent is usually placed within the peripheral orcoronary artery by an Interventional cardiologist or InterventionalRadiologist during an angioplasty procedure. Drugs commonly used in DESin order to block cell proliferation include paclitaxel or rapamycinanalogues

In some embodiments of the invention, a sGC stimulator of the inventioncan be delivered by means of a drug-eluting stent coated with said sGCstimulator. A drug-eluting stent coated with a sGC stimulator of theinvention may be useful in the prevention of stent restenosis andthrombosis during percutaneous coronary interventions. A drug-elutingstent coated with a sGC stimulator of the invention may be able toprevent smooth cell proliferation as well as to assistre-vascularization and re-generation of the endothelial tissue of theartery in which the stent is inserted.

An alternative to percutaneous coronary intervention for the treatmentof intractable angina due to coronary artery occlusive disease is theprocedure named Coronary Artery Bypass Grafting (CABG). CABG providesonly palliation of an ongoing process that is further complicated by therapid development of graft atherosclerosis. The saphenous vein graft isthe most commonly used conduit in CABG surgery. The long-term clinicalsuccess of venous CABG is hampered for three main reasons: acceleratedgraft atherosclerosis, incomplete endothelialization and thrombosis.

In some embodiments, a sGC stimulator of the invention can be used forthe prevention of saphenous graft failure during CABG. Compounds of theinvention may assist the process of endothelialization and help preventthrombosis. In this indication, the sGC stimulator is delivered locallyin the form of a gel.

The terms, “disease”, “disorder” and “condition” may be usedinterchangeably here to refer to an sGC, cGMP and/or NO mediated medicalor pathological condition.

As used herein, the terms “subject” and “patient” are usedinterchangeably. The terms “subject” and “patient” refer to an animal(e.g., a bird such as a chicken, quail or turkey, or a mammal),specifically a “mammal” including a non-primate (e.g., a cow, pig,horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and aprimate (e.g., a monkey, chimpanzee and a human), and more specificallya human. In some embodiments, the subject is a non-human animal such asa farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog,cat, guinea pig or rabbit). In some embodiments, the subject is a human.

The invention also provides a method for treating one of the abovediseases, conditions and disorders in a subject, comprisingadministering a therapeutically effective amount of a compound ofFormula I and Formula I′, or a pharmaceutically acceptable salt thereof,to the subject in need of the treatment. Alternatively, the inventionprovides the use of a compound of Formula I and Formula I′, or apharmaceutically acceptable salt thereof, in the treatment of one ofthese diseases, conditions and disorders in a subject in need of thetreatment. The invention further provides a method of making ormanufacturing a medicament useful for treating one of these diseases,conditions and disorders comprising using a compound of Formula I andFormula I′, or a pharmaceutically acceptable salt thereof.

The term “biological sample”, as used herein, refers to an in vitro orex vivo sample, and includes, without limitation, cell cultures orextracts thereof; biopsied material obtained from a mammal or extractsthereof; blood, saliva, urine, faeces, semen, tears, lymphatic fluid,ocular fluid, vitreous humour, or other body fluids or extracts thereof.

“Treat”, “treating” or “treatment” with regard to a disorder or diseaserefers to alleviating or abrogating the cause and/or the effects of thedisorder or disease. As used herein, the terms “treat”, “treatment” and“treating” refer to the reduction or amelioration of the progression,severity and/or duration of an sGC, cGMP and/or NO mediated condition,or the amelioration of one or more symptoms (preferably, one or morediscernable symptoms) of said condition (i.e. “managing” without“curing” the condition), resulting from the administration of one ormore therapies (e.g., one or more therapeutic agents such as a compoundor composition of the invention). In specific embodiments, the terms“treat”; “treatment” and “treating” refer to the amelioration of atleast one measurable physical parameter of an sGC, cGMP and/or NOmediated condition. In other embodiments the terms “treat”, “treatment”and “treating” refer to the inhibition of the progression of an sGC,cGMP and/or NO mediated condition, either physically by, e.g.,stabilization of a discernable symptom or physiologically by, e.g.,stabilization of a physical parameter, or both.

The term “preventing” as used herein refers to administering amedicament beforehand to avert or forestall the appearance of one ormore symptoms of a disease or disorder. The person of ordinary skill inthe medical art recognizes that the term “prevent” is not an absoluteterm. In the medical art it is understood to refer to the prophylacticadministration of a drug to substantially diminish the likelihood orseriousness of a condition, or symptom of the condition and this is thesense intended in this disclosure. The Physician's Desk Reference, astandard text in the field, uses the term “prevent” hundreds of times.As used therein, the terms “prevent”, “preventing” and “prevention” withregard to a disorder or disease, refer to averting the cause, effects,symptoms or progression of a disease or disorder prior to the disease ordisorder fully manifesting itself.

In one embodiment, the methods of the invention are a preventative or“pre-emptive” measure to a patient, specifically a human, having apredisposition (e.g. a genetic predisposition) to developing an sGC,cGMP and/or NO related disease, disorder or symptom.

In other embodiments, the methods of the invention are a preventative or“pre-emptive” measure to a patient, specifically a human, suffering froma disease, disorder or condition that makes him at risk of developing ansGC, cGMP or NO related disease, disorder or symptom.

The compounds and pharmaceutical compositions described herein can beused alone or in combination therapy for the treatment or prevention ofa disease or disorder mediated, regulated or influenced by sGC, cGMPand/or NO.

Compounds and compositions here disclosed are also useful for veterinarytreatment of companion animals, exotic animals and farm animals,including, without limitation, dogs, cats, mice, rats, hamsters,gerbils, guinea pigs, rabbits, horses, pigs and cattle.

In other embodiments, the invention provides a method of stimulating sGCactivity in a biological sample, comprising contacting said biologicalsample with a compound or composition of the invention. Use of a sGCstimulator in a biological sample is useful for a variety of purposesknown to one of skill in the art. Examples of such purposes include,without limitation, biological assays and biological specimen storage.

Combination Therapies

The compounds and pharmaceutical compositions described herein can beused in combination therapy with one or more additional therapeuticagents. For combination treatment with more than one active agent, wherethe active agents are in separate dosage formulations, the active agentsmay be administered separately or in conjunction. In addition, theadministration of one element may be prior to, concurrent to, orsubsequent to the administration of the other agent.

When co-administered with other agents, e.g., when co-administered withanother pain medication, an “effective amount” of the second agent willdepend on the type of drug used. Suitable dosages are known for approvedagents and can be adjusted by the skilled artisan according to thecondition of the subject, the type of condition(s) being treated and theamount of a compound described herein being used. In cases where noamount is expressly noted, an effective amount should be assumed. Forexample, compounds described herein can be administered to a subject ina dosage range from between about 0.01 to about 10,000 mg/kg bodyweight/day, about 0.01 to about 5000 mg/kg body weight/day, about 0.01to about 3000 mg/kg body weight/day, about 0.01 to about 1000 mg/kg bodyweight/day, about 0.01 to about 500 mg/kg body weight/day, about 0.01 toabout 300 mg/kg body weight/day, about 0.01 to about 100 mg/kg bodyweight/day.

When “combination therapy” is employed, an effective amount can beachieved using a first amount of a compound of Formula I and Formula I′or a pharmaceutically acceptable salt thereof and a second amount of anadditional suitable therapeutic agent.

In one embodiment of this invention, a compound of Formula I and FormulaI′ and the additional therapeutic agent are each administered in aneffective amount (i.e., each in an amount which would be therapeuticallyeffective if administered alone). In another embodiment, the compound ofFormula I and Formula I′ and the additional therapeutic agent are eachadministered in an amount which alone does not provide a therapeuticeffect (a sub-therapeutic dose). In yet another embodiment, the compoundof Formula I and Formula I′ can be administered in an effective amount,while the additional therapeutic agent is administered in asub-therapeutic dose. In still another embodiment, the compound ofFormula I and Formula I′ can be administered in a sub-therapeutic dose,while the additional therapeutic agent, for example, a suitablecancer-therapeutic agent is administered in an effective amount.

As used herein, the terms “in combination” or “co-administration” can beused interchangeably to refer to the use of more than one therapy (e.g.,one or more prophylactic and/or therapeutic agents). The use of theterms does not restrict the order in which therapies (e.g., prophylacticand/or therapeutic agents) are administered to a subject.

Co-administration encompasses administration of the first and secondamounts of the compounds in an essentially simultaneous manner, such asin a single pharmaceutical composition, for example, capsule or tablethaving a fixed ratio of first and second amounts, or in multiple,separate capsules or tablets for each. In addition, such coadministration also encompasses use of each compound in a sequentialmanner in either order. When co-administration involves the separateadministration of the first amount of a compound of Formula I andFormula I′ and a second amount of an additional therapeutic agent, thecompounds are administered sufficiently close in time to have thedesired therapeutic effect. For example, the period of time between eachadministration which can result in the desired therapeutic effect, canrange from minutes to hours and can be determined taking into accountthe properties of each compound such as potency, solubility,bioavailability, plasma half-life and kinetic profile. For example, acompound of Formula I and Formula I′ and the second therapeutic agentcan be administered in any order within about 24 hours of each other,within about 16 hours of each other, within about 8 hours of each other,within about 4 hours of each other, within about 1 hour of each other orwithin about 30 minutes of each other.

More, specifically, a first therapy (e.g., a prophylactic or therapeuticagent such as a compound described herein) can be administered prior to(e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeksbefore), concomitantly with, or subsequent to (e.g., 5 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks,4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) theadministration of a second therapy (e.g., a prophylactic or therapeuticagent such as an anti-cancer agent) to a subject.

Examples of other therapeutic agents that may be combined with acompound of this disclosure, either administered separately or in thesame pharmaceutical composition include, but are not limited to:

(1) Endothelium-derived releasing factor (EDRF);(2) NO donors such as a nitrosothiol, a nitrite, a sydnonimine, aNONOate, a N-nitrosoamine, a N-hydroxyl nitrosamine, a nitrosimine,nitrotyrosine, a diazetine dioxide, an oxatriazole 5-imine, an oxime, ahydroxylamine, a N-hydroxyguanidine, a hydroxyurea or a furoxan. Someexamples of these types of compounds include: glyceryl trinitrate (alsoknown as GTN, nitroglycerin, nitroglycerine, and trinitrogylcerin), thenitrate ester of glycerol; sodium nitroprusside (SNP), wherein amolecule of nitric oxide is coordinated to iron metal forming a squarebipyramidal complex; 3-morpholinosydnonimine (SIN-1), a zwitterioniccompound formed by combination of a morpholine and a sydnonimine;S-nitroso-N-acetylpenicillamine (SNAP), an N-acetylated amino acidderivative with a nitrosothiol functional group; diethylenetriamine/NO(DETA/NO), a compound of nitric oxide covalently linked todiethylenetriamine; and NCX 4016, an m-nitroxymethyl phenyl ester ofacetyl salicylic acid. More specific examples of some of these classesof NO donors include: the classic nitrovasodilators, such as organicnitrate and nitrite esters, including nitroglycerin, amyl nitrite,isosorbide dinitrate, isosorbide 5-mononitrate, and nicorandil;Isosorbide (Dilatrate®-SR, Imdur®, Ismo®, Isordil®, Isordil®,Titradose®, Monoket®), FK 409 (NOR-3); FR 144420 (NOR-4);3-morpholinosydnonimine; Linsidomine chlorohydrate (“SIN-1”);S-nitroso-N-acetylpenicillamine (“SNAP”); AZD3582 (CINOD lead compound),NCX 4016, NCX 701, NCX 1022, HCT 1026, NCX 1015, NCX 950, NCX 1000, NCX1020, AZD 4717, NCX 1510/NCX 1512, NCX 2216, and NCX 4040 (all availablefrom NicOx S.A.), S-nitrosoglutathione (GSNO), Sodium Nitroprusside,S-nitrosoglutathione mono-ethyl-ester(GSNO-ester),6-(2-hydroxy-1-methyl-nitrosohydrazino)-N-methyl-1-hexanamine(NOC-9) or diethylamine NONOate. Nitric oxide donors are also asdisclosed in U.S. Pat. Nos. 5,155,137, 5,366,997, 5,405,919, 5,650,442,5,700,830, 5,632,981, 6,290,981, 5,691,423 5,721,365, 5,714,511,6,511,911, and 5,814,666, Chrysselis et al. (2002) J Med Chem. 45:5406-9(such as NO donors 14 and 17), and Nitric Oxide Donors forPharmaceutical and Biological Research, Eds: Peng George Wang, TingweiBill Cai, Naoyuki Taniguchi, Wiley, 2005;(3) Other substances that enhance cGMP concentrations such asprotoporphyrin IX, arachidonic acid and phenyl hydrazine derivatives;(4) Nitric Oxide Synthase substrates: for example, n-hydroxyguanidinebased analogs, such as N[G]-hydroxy-L-arginine (NOHA), 1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine, and PR5 (1-(3,4-dimethoxy-2-chlorobenzylideneamino)-3-hydroxyguanidine); L-argininederivatives (such as homo-Arg, homo-NOHA, N-tert-butyloxy- andN-(3-methyl-2-butenyl)oxy-L-arginine, canavanine, epsilonguanidine-carpoic acid, agmatine, hydroxyl-agmatine, andL-tyrosyl-L-arginine); N-alkyl-N′-hydroxyguanidines (such asN-cyclopropyl-N′-hydroxyguanidine and N-butyl-N′-hydroxyguanidine),N-aryl-N′-hydroxyguanidines (such as N-phenyl-N′-hydroxyguanidine andits para-substituted derivatives which bear —F, —Cl, -methyl, —OHsubstituents, respectively); guanidine derivatives such as3-(trifluormethyl) propylguanidine; and others reviewed in Cali et al.(2005, Current Topics in Medicinal Chemistry 5:721-736) and disclosed inthe references cited therein;(5) Compounds which enhance eNOS transcription: for example thosedescribed in WO 02/064146, WO 02/064545, WO 02/064546 and WO 02/064565,and corresponding patent documents such as US2003/0008915,US2003/0022935, US2003/0022939 and US2003/0055093. Other eNOStranscriptional enhancers including those described in US20050101599(e.g. 2,2-difluorobenzo[1,3]dioxol-5-carboxylic acid indan-2-ylamide,and 4-fluoro-N-(indan-2-yl)-benzamide), and Sanofi-Aventis compoundsAVE3085 and AVE9488 (CA Registry NO. 916514-70-0; Schafer et al.,Journal of Thrombosis and Homeostasis 2005; Volume 3, Supplement 1:abstract number P1487);(6) NO independent heme-independent sGC activators, including, but notlimited to: BAY 58-2667 (see patent publication DE19943635)

HMR-1766 (ataciguat sodium, see patent publication WO2000002851)

S 3448

(2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-N-(4-(thiomorpholine-4-sulfonyl)-phenyl)-benzamide(see patent publications DE19830430 and WO2000002851)

and

HMR-1069 (Sanofi-Aventis).

(7) Heme-dependent sGC stimulators including, but not limited to:

YC-1 (see patent publications EP667345 and DE19744026)

Riociguat (BAY 63-2521, Adempas, commercial product, described inDE19834044)

-   -   Neliciguat (BAY 60-4552, described in WO 2003095451)

-   -   Vericiguat (BAY 1021189, clinical backup to Riociguat),    -   BAY 41-2272 (described in DE19834047 and DE19942809)

-   -   BAY 41-8543 (described in DE19834044)

-   -   Etriciguat (described in WO 2003086407)

-   -   CFM-1571 (see patent publication WO2000027394)

A-344905, its acrylamide analogue A-350619 and the aminopyrimidineanalogue A-778935.

Compounds disclosed in one of publications: US20090209556, U.S. Pat. No.8,455,638, US20110118282 (WO2009032249), US20100292192, US20110201621,U.S. Pat. Nos. 7,947,664, 8,053,455 (WO2009094242), US20100216764, U.S.Pat. No. 8,507,512, (WO2010099054) US20110218202 (WO2010065275),US20130012511 (WO2011119518), US20130072492 (WO2011149921),US20130210798 (WO2012058132) and other compounds disclosed inTetrahedron Letters (2003), 44(48): 8661-8663.(8) Compounds that inhibit the degradation of cGMP, such as:PDE5 inhibitors, such as, for example, Sildenafil (Viagra®) and otherrelated agents such as Avanafil, Lodenafil, Mirodenafil, Sildenafilcitrate (Revatio®), Tadalafil (Cialis® or Adcirca®), Vardenafil(Levitra®) and Udenafil; Alprostadil; and Dipyridamole;(9) Calcium channel blockers such as:Dihydropyridine calcium channel blockers: Amlodipine (Norvasc),Aranidipine (Sapresta), Azelnidipine (Calblock), Barnidipine (HypoCa),Benidipine (Coniel), Cilnidipine (Atelec, Cinalong, Siscard),Clevidipine (Cleviprex), Diltiazem, Efonidipine (Landel), Felodipine(Plendil), Lacidipine (Motens, Lacipil), Lercanidipine (Zanidip),Manidipine (Calslot, Madipine), Nicardipine (Cardene, Carden SR),Nifedipine (Procardia, Adalat), Nilvadipine (Nivadil), Nimodipine(Nimotop), Nisoldipine (Baymycard, Sular, Syscor), Nitrendipine (Cardif,Nitrepin, Baylotensin), Pranidipine (Acalas), Isradipine (Lomir);Phenylalkylamine calcium channel blockers: Verapamil (Calan, Isoptin)

Gallopamil (Procorum, D600); Benzothiazepines: Diltiazem (Cardizem);

Nonselective calcium channel inhibitors such as: mibefradil, bepridiland fluspirilene, fendiline;(10) Endothelin receptor antagonists (ERAs): for instance the dual(ET_(A) and ET_(B)) endothelin receptor antagonist Bosentan (marketed asTracleer®); Sitaxentan, marketed under the name Thelin®; Ambrisentan ismarketed as Letairis® in U.S; dual/nonselective endothelin antagonistActelion-1, that entered clinical trials in 2008;(11) Prostacyclin derivatives or analogues: for instance prostacyclin(prostaglandin I₂), Epoprostenol (synthetic prostacyclin, marketed asFlolan®); Treprostinil (Remodulin®), Iloprost (Ilomedin®), Iloprost(marketed as Ventavis®); oral and inhaled forms of Remodulin® that areunder development; Beraprost, an oral prostanoid available in Japan andSouth Korea;(12) Antihyperlipidemics such as: bile acid sequestrants (e.g.,Cholestyramine, Colestipol, Colestilan and Colesevelam); statins such asAtorvastatin, Simvastatin, Lovastatin, Fluvastatin, Pitavastatin,Rosuvastatin and Pravastatin; cholesterol absorption inhibitors such asEzetimibe; other lipid lowering agents such as Icosapent ethyl ester,Omega-3-acid ethyl esters, Reducol; fibric acid derivatives such asClofibrate, Bezafibrate, Clinofibrate, Gemfibrozil, Ronifibrate,Binifibrate, Fenofirate, Ciprofibrate, Choline fenofibrate; nicotinicacid derivatives such as Acipimox and Niacin; also combinations ofstatins, niacin, intestinal cholesterol absorption-inhibitingsupplements (ezetimibe and others) and fibrates; antiplatelet therapiessuch as Clopidogrel bisulfate;(13) Anticoagulants, such as the following types:

Coumarines (Vitamin K antagonists): Warfarin® (Coumadin) mostly used inthe US and UK; Acenocoumarol® and Phenprocoumon®, mainly used in othercountries; Phenindione®;

Heparin and derivative substances such as: Heparin; low molecular weightheparin, Fondaparinux and Idraparinux;

Direct thrombin inhibitors such as: Argatroban, Lepirudin, Bivalirudinand Dabigatran; Ximelagatran (Exanta®), not approved in the US;

Tissue plasminogen activators, used to dissolve clots and unblockarteries, such as Alteplase;

(14) Antiplatelet drugs: for instance thienopyridines such as Lopidogreland Ticlopidine; Dipyridamole; Aspirin;(15) ACE inhibitors, for example the following types:

Sulfhydryl-containing agents such as Captopril (trade name Capoten®),the first ACE inhibitor and Zofenopril;

Dicarboxylate-containing agents such as Enalapril (Vasotec/Renitec®);Ramipril (Altace/Tritace/Ramace/Ramiwin®); Quinapril (Accupril®),Perindopril (Coversyl/Aceon®); Lisinopril(Lisodur/Lopril/Novatec/Prinivil/Zestril®) and Benazepril (Lotensin®);

Phosphonate-containing agents such as: Fosinopril;

Naturally occurring ACE inhibitors such as: Casokinins and lactokinins,which are breakdown products of casein and whey that occur naturallyafter ingestion of milk products, especially cultured milk; TheLactotripeptides Val-Pro-Pro and Ile-Pro-Pro produced by the probioticLactobacillus helveticus or derived from casein also have ACE-inhibitingand antihypertensive functions;

Other ACE inhibitors such as Alacepril, Delapril, Cilazapril, Imidapril,Trandolapril, Temocapril, Moexipril, Spirapril,

(16) Supplemental oxygen therapy;(17) Beta blockers, such as the following types:

Non-selective agents: Alprenolol®, Bucindolol®, Carteolol®, Carvedilol®(has additional α-blocking activity), Labetalol® (has additionalα-blocking activity), Nadolol®, Penbutolol® (has intrinsicsympathomimetic activity), Pindolol® (has intrinsic sympathomimeticactivity), Oxprenonol, Acebutolol, Sotalol, Mepindolol, Celiprolol,Arotinolol, Tertatolol, Amosulalol, Nipradilol, Propranolol® andTimolol®;

β₁-Selective agents: Acebutolol® (has intrinsic sympathomimeticactivity), Atenolol®, Betaxolol®, Bisoprolol®, Celiprolol®, Dobutaminehydrochloride, Irsogladine maleate, Carvedilol, Talinolol, Esmolol®,Metoprolol® and Nebivolol®;

β₂-Selective agents: Butaxamine® (weak α-adrenergic agonist activity);

(18) Antiarrhythmic agents such as the following types:

Type I (sodium channel blockers): Quinidine, Lidocaine, Phenytoin,Propafenone

Type III (potassium channel blockers): Amiodarone, Dofetilide, Sotalol

Type V: Adenosine, Digoxin

(19) Diuretics such as: Thiazide diuretics, e.g., Chlorothiazide,Chlorthalidone, and Hydrochlorothiazide, Bendroflumethiazide,Cyclopenthiazide, Methyclothiazide, Polythiazide, Quinethazone,Xipamide, Metolazone, Indapamide, Cicletanine; Loop diuretics, such asFurosemide and Toresamide; potassium-sparing diuretics such asAmiloride, Spironolactone, Canrenoate potassium, Eplerenone andTriamterene; combinations of these agents; other diuretics such asAcetazolamid and Carperitide(20a) Direct-acting vasodilators such as Hydralazine hydrochloride,Diazoxide, Sodium nitroprusside, Cadralazine; other vasodilators such asIsosorbide dinitrate and Isosorbide 5-mononitrate;(20b) Exogenous vasodilators such as:

Adenocard®, an adenosine agonist, primarily used as an anti-arrhythmic;

Alpha blockers (which block the vasoconstricting effect of adrenaline):Alpha-1-adrenoceptor antagonists such as Prazosin, Indoramin, Urapidil,Bunazosin, Terazosin, Doxazosin

Atrial natriuretic peptide (ANP);

Ethanol;

Histamine-inducers, which complement proteins C3a, C4a and C5a work bytriggering histamine release from mast cells and basophil granulocytes;

Tetrahydrocannabinol (THC), major active chemical in marijuana which hasminor vasodilatory effects;

Papaverine, an alkaloid found in the opium poppy Papaver somniferum; b

(21) Bronchodilators: there are two major types of bronchodilator, β₂agonists and anticholinergics, exemplified below:

β₂ agonists: Salbutamol® or albuterol (common brand name: Ventolin) andTerbutaline® are short acting β₂ agonists for rapid relief of COPDsymptoms. Long acting β₂ agonists (LABAs) such as Salmeterol® andFormoterol®;

anticholinergics: Ipratropium® is the most widely prescribed shortacting anticholinergic drug. Tiotropium® is the most commonly prescribedlong-acting anticholinergic drug in COPD;

Theophylline®, a bronchodilator and phosphodiesterase inhibitor;

(22) Corticosteroids: such as beclomethasone, methylprednisolone,betamethasone, prednisone, prenisolone, triamcinolone, dexamethasone,fluticasone, flunisolide and hydrocortisone, and corticosteroid analogssuch as budesonide(23) Dietary supplements such as, for example: omega-3 oils; folid acid,niacin, zinc, copper, Korean red ginseng root, ginkgo, pine bark,Tribulus terrestris, arginine, Avena sativa, horny goat weed, maca root,muira puama, saw palmetto, and Swedish flower pollen; Vitamin C, VitaminE, Vitamin K2; Testosterone supplements, Testosterone transdermal patch;Zoraxel, Naltrexone, Bremelanotide (formerly PT-141), Melanotan II,hMaxi-K; Prelox: a Proprietary mix/combination of naturally occurringingredients, L-arginine aspartate and Pycnogenol;(24) PGD2 receptor antagonists including, but not limited to, compoundsdescribed as having PGD2 antagonizing activity in United StatesPublished Applications US20020022218, US20010051624, and US20030055077,PCT Published Applications WO9700853, WO9825919, WO03066046, WO03066047,WO03101961, WO03101981, WO04007451, WO0178697, WO04032848, WO03097042,WO03097598, WO03022814, WO03022813, and WO04058164, European PatentApplications EP945450 and EP944614, and those listed in: Torisu et al.2004 Bioorg Med Chem Lett 14:4557, Torisu et al. 2004 Bioorg Med ChemLett 2004 14:4891, and Torisu et al. 2004 Bioorg & Med Chem 200412:4685;(25) Immunosuppressants such as cyclosporine (cyclosporine A,Sandimmune® Neoral®), tacrolimus (FK-506, Prograf®), rapamycin(sirolimus, Rapamune®) and other FK-506 type immunosuppressants, andmycophenolate, e.g., mycophenolate mofetil (CellCept®);(26) Non-steroidal anti-asthmatics such as β2-agonists (e.g.,terbutaline, metaproterenol, fenoterol, isoetharine, albuterol,salmeterol, bitolterol and pirbuterol) and β2-agonist-corticosteroidcombinations (e.g., salmeterol-fluticasone (Advair®),formoterol-budesonid (Symbicort®)), theophylline, cromolyn, cromolynsodium, nedocromil, atropine, ipratropium, ipratropium bromide,leukotriene biosynthesis inhibitors (zileuton, BAY1005);(27) Non-steroidal anti-inflammatory agents (NSAIDs) such as propionicacid derivatives (e.g., alminoprofen, benoxaprofen, bucloxic acid,carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen,indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen,pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetic acidderivatives (e.g., indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin andzomepirac), fenamic acid derivatives (e.g., flufenamic acid,meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal),oxicams (e.g., isoxicam, piroxicam, sudoxicam and tenoxican),salicylates (e.g., acetyl salicylic acid and sulfasalazine) and thepyrazolones (e.g., apazone, bezpiperylon, feprazone, mofebutazone,oxyphenbutazone and phenylbutazone);(28) Cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®),rofecoxib (Vioxx®), valdecoxib, etoricoxib, parecoxib and lumiracoxib;(opioid analgesics such as codeine, fentanyl, hydromorphone,levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone,propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine andpentazocine; and(29) Anti-diabetic agents such as insulin and insulin mimetics,sulfonylureas (e.g., Glyburide, Glybenclamide, Glipizide, Gliclazide,Gliquidone, Glimepiride, Meglinatide, Tolbutamide, Chlorpropamide,Acetohexamide, Tolazamide), biguanides, e.g., metformin (Glucophage®),α-glucosidase inhibitors (such as Acarbose, Epalrestat, Voglibose,Miglitol), thiazolidinone compounds, e.g., rosiglitazone (Avandia®),troglitazone (Rezulin®), ciglitazone, pioglitazone (Actos®) andenglitazone; insulin sensitizers such as Pioglitazone and Rosiglitazone;Insulin secretagogues such as Repaglinide, Nateglinide and Mitiglinide;Incretin mimetics such as Exanatide and Liraglutide; Amylin analoguessuch as Pramlintide; glucose lowering agents such as Chromiummpicolinate (optionally combined with biotin); dipeptidyl peptidase IVinhibitors such as Sitagliptin, Vildagliptin, Saxagliptin, Alogliptinand Linagliptin; vaccines currently being developed for the treatment ofdiabetes; AVE-0277, Alum-GAD, BHT-3021, IBC-VS01; cytokine targetedtherapies in development for the treatment of diabetes such as Anakinra,Canakinumab, Diacerein, Gevokizumab, LY-2189102, MABP-1, GIT-027; drugsin development for the treatment of diabetes:

Drugs in development for the treatment of diabetes DapagliflozinAstraZeneca/Bristol- SGLT-2 Inhibitors Recommended Myers Squibb ApprovalAlogliptin Takeda Insulin Sensitizers/ Pre-Registered benzoate/metforminDipeptidyl Peptidase hydrochloride IV (CD26; DPP-IV; DP-IV) InhibitorsAnagliptin Kowa/Sanwa Dipeptidyl Peptidase Pre-Registered IV (CD26;DPP-IV; DP-IV) Inhibitors Insulin degludec Novo Nordisk Pre-RegisteredInsulin degludec/insulin Novo Nordisk Pre-Registered aspart Insulinhuman (rDNA MannKind Pre-Registered origin) inhalation powderLixisenatide Sanofi Insulin Pre-Registered Secretagogues/GLP- 1 ReceptorAgonists Recombinant human Biodel Pre-Registered insulin TeneligliptinMitsubishi Tanabe Dipeptidyl Peptidase Pre-Registered Pharma IV (CD26;DPP-IV; DP-IV) Inhibitors AVE-0277 Andromeda Biotech/ Phase III TevaAlbiglutide GlaxoSmithKline GLP-1 Receptor Phase III AgonistsAleglitazar Roche PPARalpha Agonists/ Phase III PPARgamma AgonistsAtorvastatin GlaxoSmithKline K(ATP) Channel Phase IIIcalcium/glimepiride Blockers/Dipeptidyl Peptidase IV (CD26; DPP-IV;DP-IV) Inhibitors/HMG-CoA Reductase Inhibitors/ TNFSF6 ExpressionInhibitors BYK-324677 Nycomed Phase III Balaglitazone Dr. Reddy'sInsulin Sensitizers/ Phase III Laboratories PPARgamma Partial AgonistsCSG-452 Chugai SGLT-2 Inhibitors Phase III Pharmaceutical CanagliflozinJohnson & Johnson/ SGLT-2 Inhibitors Phase III Mitsubishi Tanabe PharmaCanagliflozin/metformin Johnson & Johnson SGLT-2 Inhibitors/ Phase IIIhydrochloride Insulin Sensitizers Dapagliflozin/MetforminAstraZeneca/Bristol- SGLT-2 Inhibitors/ Phase III hydrochloride MyersSquibb Insulin Sensitizers Dulaglutide Lilly Insulin Phase IIISecretagogues/GLP-1 Receptor Agonists Empagliflozin BoehringerIngelheim/ SGLT-2 Inhibitors Phase III Lilly Empagliflozin/linagliptinBoehringer Ingelheim/ SGLT-2 Inhibitors/ Phase III Lilly DipeptidylPeptidase IV (CD26; DPP-IV; DP-IV) Inhibitors Gemigliptin LG LifeSciences Dipeptidyl Peptidase Phase III IV (CD26; DPP-IV; DP-IV)Inhibitors Hepatic-directed vesicle Diasome Phase III insulinPharmaceuticals Human isophane insulin Wockhardt Phase III IN-105 BioconPhase III Insulin Novo Nordisk Insulin Phase III degludec/liraglutideSecretagogues/GLP-1 Receptor Agonists Insulin glargine Sanofi Phase IIIIpragliflozin L-proline Astellas Pharma/ SGLT-2 Inhibitors Phase IIIKotobuki LY-2605541 Lilly Phase III LY-2963016 Lilly Phase IIILixisenatide/Insulin Sanofi Insulin Phase III glargineSecretagogues/GLP-1 Receptor Agonists Lobeglitazone sulfate Chong KunDang PPARalpha Agonists/ Phase III Pharm (CKD Pharm) PPARgammaAgonists/Insulin Sensitizers Luseogliflozin Taisho SGLT-2 InhibitorsPhase III Otelixizumab Tolerx Anti-CD3 Phase III Ranolazine GileadSodium Channel Phase III Blockers Recombinant human National Instituteof Phase III insulin Health Sciences Sitagliptin phosphate Merck & Co.PPARgamma Phase III monohydrate/pioglitazone Agonists/Insulinhydrochloride Sensitizers/ Dipeptidyl Peptidase IV (CD26; DPP-IV; DP-IV)Inhibitors Sitagliptin/atorvastatin Merck & Co. Dipeptidyl PeptidasePhase III calcium IV (CD26; DPP-IV; DP-IV) Inhibitors/ HMG-CoA ReductaseInhibitors/TNFSF6 Expression Inhibitors TAK-875 Takeda Free Fatty AcidPhase III Receptor 1 (FFAR1; GPR40) Agonists/ Insulin SecretagoguesTT-401 7TM Pharma Cannabinoid CB1 Phase I Antagonists TT-401 TransitionPhase I Therapeutics ZYH-2 Cadila Healthcare PPARalpha Ligands/ Phase I(d/b/a Zydus Cadila) PPARgamma Ligands ZYO-1 Cadila HealthcareCannabinoid CB1 Phase I (d/b/a Zydus Cadila) Antagonists 701645 CellonisPhase I Biotechnologies 701499 Cellonis Phase I Biotechnologies 743300University of Phase I California, San Francisco 448661 University ofPhase I Pittsburgh AD-1 National Institute Clinical Pharma Res DevColesevelam Daiichi Sankyo Bile Acid Clinical hydrochloride SequestrantsDBPR-108 National Health IND Filed Research Institutes/ ScinoPharmNodlin Biolaxy IND Filed PSN-491 Prosidion Glucose-Dependent IND FiledInsulinotropic Receptor (GDIR, GPR119) Agonists/ Dipeptidyl Peptidase IV(CD26; DPP-IV; DP-IV) Inhibitors Tolimidone Melior Discovery Lyn KinaseActivators IND Filed ZYD-1 Cadila Healthcare GLP-1 Receptor IND Filed(d/b/a Zydus Cadila) Agonists ZYOG-1 Cadila Healthcare GLP-1 ReceptorIND Filed (d/b/a Zydus Cadila) Agonists(30) HDL cholesterol-increasing agents such as Anacetrapib, MK-524A,CER-001, DRL-17822, Dalcetrapib, JTT-302, RVX-000222, TA-8995;(31) Antiobesity drugs such as Methamphetamine hydrochloride,Amfepramone hydrochloride (Tenuate®), Phentermine (Ionamin®),Benzfetamine hydrochloride (Didrex®), Phendimetrazine tartrate(Bontril®, Prelu-2 ®, Plegine®), Mazindol (Sanorex®), Orlistat(Xenical®), Sibutramine hydrochloride monohydrate (Meridia®, Reductil®),Rimonabant (Acomplia®), Amfepramone, Chromium picolinate, RM-493,TZP-301; combination such as Phentermine/Topiramate,Bupropion/Naltrexone, Sibutramine/Metformin, Bupropion SR/Zonisamide SR,Salmeterol, xinafoate/fluticasone propionate; Lorcaserin hydrochloride,Phentermine/topiramate, Bupropion/naltrexone, Cetilistat, Exenatide,KI-0803, Liraglutide, Metformin hydrochloride, Sibutramine/Metformin,876167, ALS-L-1023, Bupropion SR/Zonisamide SR, CORT-108297,Canagliflozin, Chromium picolinate, GSK-1521498, LY-377604, Metreleptin,Obinepitide, P-57AS3, PSN-821, Salmeterol xinafoate/fluticasonepropionate, Sodium tungstate, Somatropin (recombinant), TM-30339,TTP-435, Tesamorelin, Tesofensine, Velneperit, Zonisamide, BMS-830216,ALB-127158, AP-1030, ATHX-105, AZD-2820, AZD-8329, Beloranibhemioxalate, CP-404, HPP-404, ISIS-FGFR4Rx, Insulinotropin, KD-3010PF,05212389, PP-1420, PSN-842, Peptide YY3-36, Resveratrol, S-234462;S-234462, Sobetirome, TM-38837, Tetrahydrocannabivarin, ZYO-1,beta-Lapachone;(32) Angiotensin receptor blockers such as Losartan, Valsartan,Candesartan cilexetil, Eprosaran, Irbesartan, Telmisartan, Olmesartranmedoxomil, Azilsartan medoxomil;(33) Renin inhibitors such as Aliskiren hemifumirate;(34) Centrally acting alpha-2-adrenoceptor agonists such as Methyldopa,Clonidine, Guanfacine;(35) Adrenergic neuron blockers such as Guanethidine, Guanadrel;(36) Imidazoline I-1 receptor agonists such as Rimenidine dihydrogenphosphate and Moxonidine hydrochloride hydrate;(37) Aldosterone antagonists such as Spironolactone and Eplerenone(38) Potassium channel activators such as Pinacidil(39) Dopamine D1 agonists such as Fenoldopam mesilate; Other dopamineagonists such as Ibopamine, Dopexamine and Docarpamine;(40) 5-HT2 antagonists such as Ketanserin;(41) Drugs that are currently being developed for the treatment ofarterial hypertension:

Drugs in development for the treatment of hypertension Azilsartan TakedaAngiotensin AT1 Registered Antagonists/ Angiotensin AT2 Antagonists/Insulin Sensitizers Amlodipine besylate/irbesartan Dainippon SumitomoAngiotensin AT1 Pre-Registered Pharma Antagonists/ Calcium ChannelBlockers Azilsartan/amlodipine besilate Takeda Angiotensin AT1 Phase IIIAntagonists/ Insulin Sensitizers/ Calcium Channel BlockersCilnidipine/valsartan Ajinomoto/Mochida Angiotensin AT1 Phase IIIAntagonists/ Calcium Channel Blockers Fimasartan Boryung Angiotensin AT1Phase III Antagonists Irbesartan/atorvastatin Hanmi Angiotensin AT1Phase III Antagonists/ Dipeptidyl Peptidase IV (CD26; DPP-IV; DP-IV)Inhibitors/HMG- CoA Reductase Inhibitors/ TNFSF6 Expression InhibitorsIrbesartan/trichlormethiazide Shionogi Angiotensin AT1 Phase IIIAntagonists Losartan Merck & Co. Angiotensin AT1 Phase IIIpotassium/hydrochlorothiazide/ Antagonists/ amlodipine besylate CalciumChannel Blockers Pratosartan Boryung Angiotensin AT1 Phase IIIAntagonists ACT-280778 Actelion Phase II Amiloride HemodynamicMineralocorticoid Phase II hydrochloride/spironolactone TherapeuticsReceptor (MR) Antagonists/ Na+/H+ Exchanger (NHE) Inhibitors/ EpithelialSodium Channels (ENaC) Blockers/ K(V)1.5 Channel Blockers/ K(V)4.3Channel Blockers Angiotensin vaccine/CoVaccine HT BTG Phase IICYT006-AngQb Cytos Biotechnology Anti-Angiotensin Phase II IICholecalciferol Emory University Phase II Cobiprostone Sucampo CIC-2Channel Phase II Pharmaceuticals Activators INT-001 IntelGenx Phase IILCZ-696 Novartis Angiotensin AT1 Phase II Antagonists/ Neprilysin(Enkephalinase, Neutral Endopeptidase, NEP) Inhibitors LFF-269 NovartisPhase II Octreotide acetate Chiasma Growth Hormone Phase II ReleaseInhibitors/ Somatostatin Agonists PL-3994 Palatin Technologies AtrialNatriuretic Phase II Peptide A (NPR1; Guanylate Cyclase A) ReceptorAgonists Rostafuroxine Sigma-Tau Phase II SLx-2101 NT Life SciencesPhosphodiesterase Phase II V (PDE5A) Inhibitors TBC-3711 EncysiveEndothelin ETA Phase II Pharmaceuticals Receptor Antagonists UdenafilDong-A/Falk Pharma Phosphodiesterase Phase II V (PDE5A) InhibitorsAtorvastatin calcium/losartan HanAll BioPharma Angiotensin AT1 Phase Ipotassium Antagonists/ Dipeptidyl Peptidase IV (CD26; DPP-IV; DP-IV)Inhibitors/HMG- CoA Reductase Inhibitors/ TNFSF6 Expression InhibitorsBIA-5-1058 BIAL Dopamine beta- Phase I monooxygenase Inhibitors CS-3150Daiichi Sankyo Phase I DSP-9599 Dainippon Sumitomo Renin InhibitorsPhase I Pharma MK-1597 Actelion/Merck & Co. Renin Inhibitors Phase IMK-4618 Merck & Co. Phase I MK-5478 Merck & Co. Phase I MK-7145 Merck &Co. Phase I MK-8266 Merck & Co. Phase I MK-8457 Merck & Co. Phase IMP-157 Mitsubishi Tanabe Angiotensin AT2 Phase I Pharma Agonists MT-3995Mitsubishi Tanabe Mineralocorticoid Phase I Pharma Receptor (MR)Antagonists Mirodenafil hydrochloride SK Chemicals PhosphodiesterasePhase I V (PDE5A) Inhibitors NV-04 Novogen Antioxidants Phase INifedipine/Candesartan cilexetil Bayer Angiotensin AT1 Phase IAntagonists/ Calcium Channel Blockers/ Antioxidants QGC-001 QuantumGenomics Glutamyl Phase I Aminopeptidase (Aminopeptidase A) InhibitorsRDX-5791 Ardelyx Na+/H+ Phase I Exchanger type 3 (NHE-3) InhibitorsTAK-272 Takeda Renin Inhibitors Phase I TAK-591 Takeda Angiotensin AT2Phase I Antagonists VTP-27999 Vitae Pharmaceuticals Renin InhibitorsPhase I Vasomera PhaseBio VPAC2 (VIP2) Phase I Agonists(42) Vasopressin antagonists such as Tolvaptan;(43) Calcium channel sensitizers such as Levosimendan or activators suchas Nicorandil;(44) PDE-3 inhibitors such as Amrinone, Milrinone, Enoximone,Vesnarinone, Pimobendan, Olprinone;(45) Adenylate cyclase activators such as Colforsin dapropatehydrochloride;(46) Positive inotropic agents such as Digoxin and Metildigoxin;metabolic cardiotonic agents such as Ubidecarenone; brain natureticpeptides such as Nesiritide;(47) Drugs that are currently in development for the treatment of heartfailure:

Drugs in development for the treatment of heart failure Bucindolol ARCAbeta-Adrenoceptor Pre- hydrochloride Antagonists Registered AliskirenNovartis Renin Inhibitors Phase III hemifumarate Ferric Vifor Phase IIIcarboxymaltose LCZ-696 Novartis Angiotensin AT1 Phase III Antagonists/Neprilysin (Enkephalinase, Neutral Endopeptidase, NEP) InhibitorsNeuregulin-1 Zensun Phase III Olmesartan Tohoku University AngiotensinAT1 Phase III medoxomil Antagonists C3BS-CQR-1 Cardio3 Phase II/IIIBioSciences MyoCell Bioheart Phase II/III Serelaxin Novartis PhaseII/III AAV1/ AmpliPhi Phase II SERCA2a Biosciences/ Celladon/Mount SinaiSchool of Medicine Albiglutide GlaxoSmithKline GLP-1 Receptor Phase IIAgonists Allogeneic Mesoblast Phase II mesenchymal precursor cellsAlsterMACS Miltenyi Biotec Phase II BAY-94-8862 Bayer MineralocorticoidPhase II Receptor (MR) Antagonists COR-1 Corimmun Phase II CXL-1020Cardioxyl Nitric Oxide Phase II Pharmaceuticals Donors Cenderitide NileTherapeutics Guanylate Phase II Cyclase Activators EndometrialERCell/Medistem Phase II regenerative cells JNJ-39588146 Johnson &Johnson Phase II Omecamtiv Amgen/Cytokinetics Cardiac Myosin Phase IImecarbil Activators PL-3994 Palatin Atrial Natriuretic Phase IITechnologies Peptide A (NPR1; Guanylate Cyclase A) Receptor AgonistsRemestemcel-L Osiris Phase II TRV-120027 Trevena Angiotensin AT1 PhaseII Receptor Ligands Urocortin 2 Neurocrine CRF2 Agonists Phase IIBiosciences AAV6-CMV- Imperial College Phase I/II SERCA2a AnakinraNational Institutes IL-1 Receptor Phase I/II of Health (NIH) AntagonistsLipiCell Bioheart/Institute Phase I/II de Medicina Regenerativa ALD-201Cytomedix/Texas Phase I Heart Institute BAY-1021189/ Bayer Phase IIVericiguat BAY-1067197 Bayer Adenine Receptor Phase I AgonistsBAY-86-8050 Bayer Drugs Acting on Phase I Vasopressin (AVP) ReceptorsBIA-5-1058 BIAL Dopamine beta- Phase I monooxygenase Inhibitors CSCsUniversity of Phase I Louisville Calcitonin gene VasoGenix Phase Irelated peptide JVS-100 Juventas Phase I Therapeutics MyoCell SDF-Bioheart Phase I 1 Myoblast Advanced Cell Phase I Technology (ACT)RO-1160367 Serodus 5-HT4 Phase I Antagonists RecombinantAcorda/Vanderbilt Phase I human glial University growth factor 2[18F]LMI- Lantheus Medical Phase I 1195 Imaging 677950 Kyoto PrefecturalPhase I University of Medicine(48) Drugs currently in development for the treatment of pulmonaryhypertension:

Drugs in development for the treatment of pulmonary hypertensionImatinib Novartis Breast Cancer-Resistant Protein (BCRP; Pre-Registeredmesylate ABCG2) Inhibitors/Abl Kinase Inhibitors/ AngiogenesisInhibitors/Bcr-Abl Kinase Inhibitors/CSF1R (c-FMS) Inhibitors/KIT(C-KIT) Inhibitors/Apoptosis Inducers/ PDGFRalpha Inhibitors/PDGFRbetaInhibitors/Inhibitors of Signal Transduction Pathways TreprostinilUnited Prostacyclin Analogs Pre-Registered diethanolamine TherapeuticsGSK-1325760A GlaxoSmithKline Phase III Macitentan Actelion EndothelinETA Receptor Antagonists/ Phase III Endothelin ETB Receptor AntagonistsRiociguat/ Bayer Guanylate Cyclase Activators Approved 2013 AdempasSelexipag Actelion/Nippon Prostanoid IP Agonists Phase III ShinyakuUdenafil Dong-A Phosphodiesterase V (PDE5A) Inhibitors Phase IIIL-Citrulline Nat Heart, Lung, Phase II/III and Blood Institute/Vanderbilt University BQ-123 Brigham & Endothelin ETA ReceptorAntagonists Phase II Women's Hospital Cicletanine Gilead Phase IIFasudil Asahi Kasei Rho Kinase Inhibitors/Calcium Phase II hydrochlorideSensitizers Nilotinib Novartis Bcr-Abl Kinase Inhibitors/Apoptosis PhaseII hydrochloride Inducers/Inhibitors of Signal monohydrate TransductionPathways PRX-08066 Clinical Data 5-HT2B Antagonists Phase II TergurideErgoNex 5-HT2A Antagonists/5-HT2B Phase II Pharma Antagonists/DopamineAutoreceptor Agonists/Dopamine D2 Receptor Partial Agonists/ProlactinSecretion Inhibitors Tezosentan Actelion Endothelin ETA ReceptorAntagonists/ Phase II disodium Endothelin ETB Receptor AntagonistsAnakinra Virginia IL-1 Receptor Antagonists Phase I/II CommonwealthUniversity (VCU) Simvastatin Imperial College HDL-Cholesterol IncreasingAgents/ Phase I/II HMG-CoA Reductase Inhibitors 99mTC- Montreal HeartPhase I PulmoBind Institute (MHI) APD-811 Arena Prostanoid IP AgonistsPhase I Sorafenib Bayer Raf kinase B Inhibitors/Raf kinase C Phase IInhibitors/Angiogenesis Inhibitors/Flt3 (FLK2/STK1) Inhibitors/VEGFR-1(Flt-1) Inhibitors/KIT (C-KIT) Inhibitors/ VEGFR-2 (FLK-1/KDR)Inhibitors/VEGFR- 3 (FLT4) Inhibitors/PDGFRbeta Inhibitors/RETInhibitors/Inhibitors of Signal Transduction Pathways TriplelastatProteo Biotech Elastase Inhibitors Phase I(49) Drugs in current development for the treatment of female sexualdysfunction:

Drugs in active development for the treatment of female sexualdysfunction Alprostadil Apricus Phase III Biosciences/ VIVUS PrasteroneEndoCeutics/ HSD11B1 Phase III Monash Expression University InhibitorsTestosterone BioSante Androgen Phase III transdermal gel ReceptorAgonists Bremelanotide Palatin Melanocortin Phase II Technologies MC3Receptor Agonists/ Melanocortin MC4 Receptor Agonists Pill-PlusPantarhei Phase II Bioscience Testosterone Acrux Androgen Phase II MDTSReceptor Agonists Estradiol/ BioSante Estrogen Phase I testosteroneReceptor (ER) Agonists/ Androgen Receptor Agonists LGD-2941 LigandSelective Phase I Androgen Receptor Modulators (SARM) Lidocaine/heparinUrigen Phase I OnabotulinumtoxinA Allergan Phase I(50) Drugs used for the treatment of erectile dysfunction such asAlprostadil, Aviptadil, Phentolamine mesilate, Weige, Alprostadil;(51) Drugs currently in development for the treatment of male sexualdysfunction:

Drugs in active development for the treatment of erectile dysfunctionFluvastatin Novartis Apoptosis Phase III sodium Inducers/ HMG-CoAReductase Inhibitors Lodenafil Cristalia Phosphodiesterase V Phase IIIcarbonate (PDE5A) Inhibitors EFLA-400 Chonbuk Phase II/III NationalUniversity Hospital Apomorphine Vectura Dopamine D2 Phase IIhydrochloride Agonists LY-900010 Lilly Phosphodiesterase V Phase II(PDE5A) Inhibitors/ Selective Androgen Receptor Modulators (SARM)Nitroglycerin Futura Medical Phase II RX-10100 Rexahn Drugs Acting onPhase II Dopaminergic Transmission/ Drugs Acting on SerotonergicTransmission YHD-1023 Yuhan Phase II INT-007 IntelGenx Phase ILY-2452473 Lilly Selective Phase I Androgen Receptor Modulators (SARM)hMaxi-K Albert Einstein Phase I College of Medicine/Ion ChannelInnovations/ Mount Sinai School of Medicine KH-204 KMSI Clinical(51) Drugs in development for the treatment of sleep apnea:

Drugs in development for the treatment of sleep apnea CX-1739 CortexAMPA Receptor Phase II Modulators Phentermine/ VIVUS AMPA Phase IItopiramate Antagonists/ Kainate Antagonists/ Sodium Channel Blockers/Carbonic Anhydrase Type II Inhibitors AVE-0118 Sanofi Potassium Phase IChannel Blockers Suvorexant Merck & Co. Orexin Receptor Phase IAntagonists(52) Drugs currently in development for the treatment of metabolicsyndrome:

Antihyperlipidemic drugs under active development for the treatment ofpatients with metabolic syndrome GFT-505 Genfit PPARalpha Phase IIAgonists/ PPARdelta Agonists MBX-8025 Metabolex PPARdelta Phase IIAgonists Pitavastatin Kowa APOA1 Phase I calcium Expression Enhancers/HMG-CoA Reductase Inhibitors/ SPP1 (Osteopontin) Expression Inhibitors(53) Antiobesity drugs:

Drugs marketed for the treatment of obesity Methamphetamine AbbottNoradrenergic, 1943 (U.S.) hydrochloride alpha- and (Desoxyn)beta-adrenoceptor agonist Amfepramone Sanofi Noradrenergic 1959 (U.S.)hydrochloride release stimulant (Tenuate) Phentermine UCB Noradrenergic1959 (U.S.) (Ionamin) Celltech release stimulant Benzfetamine PfizerNoradrenergic 1960 (U.S.) hydrochloride release stimulant (Didrex)Phendimetrazine Pfizer Noradrenergic 1961 (U.S.) tartrate (Bontril,release stimulant Prelu-2, Plegine) Mazindol Novartis Noradrenergic 1973(U.S.) (Sanorex) reuptake inhibitor Orlistat Roche Pancreatic lipase1998 (New (Xenical) inhibitor Zealand)(54) Drugs used for the treatment of Alzheimer's disease: e.g.,cholinesterase inhibitors prescribed for mild to moderate Alzheimer'sdisease, including Razadyne® (galantamine), Exelon® (rivastigmine), andAricept® (donepezil), Cognex® (tacrine); Namenda® (memantine), anN-methyl D-aspartate (NMDA) antagonist, and Aricept®, prescribed totreat moderate to severe Alzheimer's disease; vitamin E (ananti-oxidant).(55) Antidepressants: tricyclic antidepressants such as amitriptyline(Elavil®), desipramine (Norpramin®), imipramine (Tofranil®), amoxapine(Asendin®), nortriptyline; the selective serotonin reuptake inhibitors(SSRI's) such as paroxetine (Paxil®), fluoxetine (Prozac®), sertraline(Zoloft®), and citralopram (Celexa®); and others such as doxepin(Sinequan®) and trazodone (Desyrel®); SNRIs (e.g., venlafaxine andreboxetine); dopaminergic antidepressants (e.g., bupropion andamineptine).(56) Neuroprotective agents: e.g., memantine, L-dopa, bromocriptine,pergolide, talipexol, pramipexol, cabergoline, neuroprotective agentscurrently under investigation including anti-apoptotic drugs (CEP 1347and CTCT346), lazaroids, bioenergetics, antiglutamatergic agents anddopamine receptors. Other clinically evaluated neuroprotective agentsare, e.g., the monoamine oxidase B inhibitors selegiline and rasagiline,dopamine agonists, and the complex I mitochondrial fortifier coenzymeQ10.(57) Antipsychotic medications: e.g., ziprasidone (Geodon™), risperidone(Risperdal™), and olanzapine (Zyprexa™)

Kits

The compounds and pharmaceutical formulations described herein may becontained in a kit. The kit may include single or multiple doses of twoor more agents, each packaged or formulated individually, or single ormultiple doses of two or more agents packaged or formulated incombination. Thus, one or more agents can be present in first container,and the kit can optionally include one or more agents in a secondcontainer. The container or containers are placed within a package, andthe package can optionally include administration or dosageinstructions. A kit can include additional components such as syringesor other means for administering the agents as well as diluents or othermeans for formulation. Thus, the kits can comprise: a) a pharmaceuticalcomposition comprising a compound described herein and apharmaceutically acceptable carrier, vehicle or diluent; and b) acontainer or packaging. The kits may optionally comprise instructionsdescribing a method of using the pharmaceutical compositions in one ormore of the methods described herein (e.g. preventing or treating one ormore of the diseases and disorders described herein). The kit mayoptionally comprise a second pharmaceutical composition comprising oneor more additional agents described herein for co therapy use, apharmaceutically acceptable carrier, vehicle or diluent. Thepharmaceutical composition comprising the compound described herein andthe second pharmaceutical composition contained in the kit may beoptionally combined in the same pharmaceutical composition.

A kit includes a container or packaging for containing thepharmaceutical compositions and may also include divided containers suchas a divided bottle or a divided foil packet. The container can be, forexample a paper or cardboard box, a glass or plastic bottle or jar, are-sealable bag (for example, to hold a “refill” of tablets forplacement into a different container), or a blister pack with individualdoses for pressing out of the pack according to a therapeutic schedule.It is feasible that more than one container can be used together in asingle package to market a single dosage form. For example, tablets maybe contained in a bottle which is in turn contained within a box.

An example of a kit is a so-called blister pack. Blister packs are wellknown in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process, recesses are formed in theplastic foil. The recesses have the size and shape of individual tabletsor capsules to be packed or may have the size and shape to accommodatemultiple tablets and/or capsules to be packed. Next, the tablets orcapsules are placed in the recesses accordingly and the sheet ofrelatively stiff material is sealed against the plastic foil at the faceof the foil which is opposite from the direction in which the recesseswere formed. As a result, the tablets or capsules are individuallysealed or collectively sealed, as desired, in the recesses between theplastic foil and the sheet. Preferably the strength of the sheet is suchthat the tablets or capsules can be removed from the blister pack bymanually applying pressure on the recesses whereby an opening is formedin the sheet at the place of the recess. The tablet or capsule can thenbe removed via said opening.

It may be desirable to provide written memory aid containing informationand/or instructions for the physician, pharmacist or subject regardingwhen the medication is to be taken. A “daily dose” can be a singletablet or capsule or several tablets or capsules to be taken on a givenday. When the kit contains separate compositions, a daily dose of one ormore compositions of the kit can consist of one tablet or capsule whilea daily dose of another or more compositions of the kit can consist ofseveral tablets or capsules. A kit can take the form of a dispenserdesigned to dispense the daily doses one at a time in the order of theirintended use. The dispenser can be equipped with a memory-aid, so as tofurther facilitate compliance with the regimen. An example of such amemory-aid is a mechanical counter which indicates the number of dailydoses that have been dispensed. Another example of such a memory-aid isa battery-powered micro-chip memory coupled with a liquid crystalreadout, or audible reminder signal which, for example, reads out thedate that the last daily dose has been taken and/or reminds one when thenext dose is to be taken.

EXAMPLES

All references provided in the Examples are herein incorporated byreference. As used herein, all abbreviations, symbols and conventionsare consistent with those used in the contemporary scientificliterature. See, e.g. Janet S. Dodd, ed., The ACS Style Guide: A Manualfor Authors and Editors, 2^(nd) Ed., Washington, D.C.: American ChemicalSociety, 1997, herein incorporated in its entirety by reference.

Example 1: Syntheses of the Compounds of Table 1A, Table 1B, Table ICand Table ID

Step 1:

Dione enolate formation: To a solution of ketone A in THF cooled to −78°C., LiHMDS (e.g., 0.9 equiv, 1.0 M in toluene) was added dropwise viasyringe. The reaction was allowed to warm to 0° C., then charged withdiethyl oxalate (1.2 equiv). At this time, the reaction was warmed toroom temperature and stirred at that temperature until judged complete(e.g., using either TLC or LC/MS analysis). Once the reaction wascomplete (reaction time was typically 45 minutes), the product dioneenolate B was used “as-is” in Step 2, i.e., the cyclization step,without any further purification.

Step 2:

Pyrazole formation: Dione enolate B was diluted with ethanol andconsecutively charged with HCl (e.g., 3 equiv, 1.25 M solution inethanol) and arylhydrazine hydrate (e.g., 1.15 equiv). The reactionmixture was heated to 70° C. and stirred at this temperature untilcyclization was deemed complete (e.g., by LC/MS analysis, typically 30minutes). Once complete, the reaction mixture was treated carefully withsolid sodium bicarbonate (e.g., 4 equiv) and diluted withdichloromethane and water. Layers were separated, and aqueous layer wasfurther diluted with water before extraction with dichloromethane (3×).The combined organics were washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo. The resulting pyrazole C was thenpurified by SiO₂ chromatography using an appropriate gradient of EtOAcin hexanes.

Step 3:

Amidine formation: To a suspension of NH₄Cl (e.g., 5 equiv) in toluenecooled to 0° C. was added AlMe₃ (e.g., 5 equiv, 2.0 M solution intoluene) dropwise via syringe. The reaction was allowed to warm to roomtemperature, and stirred at this temperature until no more bubbling wasobserved. Pyrazole C was added in 1 portion to the reaction mixture,heated to 110° C., and stirred at this temperature until judged complete(e.g., using either TLC or LC/MS analysis). Once complete, the reactionwas cooled, treated with excess methanol, and stirred vigorously for 1hour at room temperature. The thick slurry was filtered, and theresulting solid cake was washed with methanol. The filtrate wasconcentrated in vacuo, and the resulting solids were re-suspended in anethyl acetate:isopropyl alcohol=5:1 solvent mixture. The reaction wasfurther treated with saturated sodium carbonate solution, and stirredfor 10 minutes before the layers are separated. The aqueous layer wasextracted with the ethyl acetate:isopropyl alcohol=5:1 solvent mixture(3×), and the combined organics were washed with brine. The organicswere further dried over MgSO₄, filtered, and the solvent removed invacuo. The product amidine D was used as-is in subsequent steps withoutfurther purification.

Step 4:

Pyrimidone formation: Amidine D was suspended in ethanol, and stirredvigorously at 23° C. to encourage full solvation. The reaction wasfurther treated with sodium 3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olate(e.g., 3 equiv.), and the flask was equipped with a reflux condenser.The reaction was placed into a pre-heated oil bath maintained at 90° C.and stirred until full consumption of starting material was observed onthe LC/MS (reaction times were typically 1 h). The contents were cooledto 23° C., and the reaction mixture acidified with HCl (e.g., 3 equiv.,1.25M solution in EtOH). The mixture was stirred for 30 minutes, and themajority of the solvent was removed in vacuo. Contents were re-suspendedin ether and water (1:1 mixture), and the resulting slurry was stirredfor 20 min. The suspension was vacuum filtered, and the solid cake wasrinsed with additional water and ether and dried on high vacuumovernight. The resulting pyrimidone E was used as-is in subsequent stepswithout further purification.

A solution of amino nucleophile (3 equiv.), triethylamine (10 equiv.),and Intermediate 1 (1 equiv.) was stirred in dioxane and water (2:1ratio) at 90° C. until complete consumption of starting material wasobserved by LC/MS. The solution was diluted with aqueous 1N hydrochloricacid and dichloromethane. The layers were then separated and the aqueouslayer was extracted with dichloromethane. The organics were combined,dried over magnesium sulfate, filtered, and the solvent was removed invacuo. Purification yielded the desired product.

A mixture of Intermediate 2 (this intermediate was described inpreviously published patent application WO2012/3405 A1; 1 equivalent)and carboxylic acid (1.1 equivalent) in N,N-dimethylformamide wastreated with triethylamine (4 equivalent) followed by a 50% in ethylacetate solution of propylphosphonic anhydride (T3P, 1.4 equivalent).The reaction was heated to 80° C. for 24 h, after which the reaction wasdiluted with water and 1N hydrochloric acid solution. Contents wereextracted with dichloromethane, then ethyl acetate. The combined organiclayers were dried over sodium sulfate, filtered, and concentrated invacuo. Purification yielded the desired product.

Synthesis of Intermediate 1

A suspension of5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-pyrimidin-4-ol(generated via general procedure A, using 1-(isoxazol-3-yl)ethanone instep 1 and 2-fluorobenzylhydrazine in step 2, 11.5 g, 32.4 mmol, 1equiv.) in phosphoryl trichloride (60.3 mL, 647 mmol, 20 equiv.) washeated at 60° C. for 3 h. The solution was cooled to 23° C., and pouredportionwise over the course of 15 min into ice water (800 mL) withstirring. After completion of addition, contents were stirred for anadditional 15 min, and diluted with dichloromethane (500 mL). The layerswere separated and the aqueous layer was extracted with dichloromethane(2×200 mL). The organics were dried over magnesium sulfate, filtered,and the solvent was removed in vacuo to yield Intermediate 1 (12.5 g,103% yield) as a tan solid.

¹H NMR (500 MHz, DMSO-d₆) δ 9.11 (d, 1H), 9.04 (s, 1H), 7.71-7.68 (m,1H), 7.37-7.30 (m, 2H), 7.25-7.20 (m, 1H), 7.12 (t, 1H), 6.92 (td, 1H),5.95 (s, 2H).

Compound I-248

A mixture of Intermediate 1 (48 mg, 1 equiv.),(R)-3-methyl-2-((methylamino)methyl) butanoic acid, (99 mg, TFA salt, 3equiv.), and triethylamine (0.177 mL, 10 equiv.) was heated to 100° C.as a solution in dioxane/water (2:1) for 20 h, following GeneralProcedure B The contents were treated with 3N HCl, and partitionedbetween a 1:1 mixture of dichloromethane and water. The layers wereseparated, and the aqueous layer was treated with a small amount ofsodium chloride. The aqueous layer was then extracted withdichloromethane (×3), and the organic portions were combined and washedwith brine. The mixture was dried over MgSO₄, filtered, and concentratedin vacuo. The crude material was purified via silica gel chromatographyutilizing a 0-10% methanol/dichloromethane gradient to deliver thedesired compound, Compound I-248 (20 mg, 93%) as an off-white solid.

¹H-NMR (500 MHz, MeOD) δ 8.74 (d, 1H), 8.09 (d, 1H), 7.38 (s, 1H),7.29-7.23 (m, 1H), 7.10-7.05 (m, 1H), 7.02 (td, 1H), 6.87-6.83 (m, 1H),6.83 (d, 1H), 5.98-5.89 (m, 2H), 4.15 (dd, 1H), 3.81 (dd, 1H), 3.33 (d,3H), 2.72-2.65 (m, 1H), 1.94 (dq, 1H), 1.09 (d, 3H), 1.01 (d, 3H).

Compound I-250

The title compound was prepared following general procedure B, except1-((methylamino)methyl) cyclopropanecarboxylic acid (as the TFA salt)was the amine reactant, contents were heated to 100° C. for 20 h, andthe aqueous layer during workup was treated with sodium chloride. Thecrude material was purified via silica gel chromatography utilizing a0-10% methanol/dichloromethane gradient to deliver the desired compound,Compound I-250 (40 mg, 54%) as an off-white solid.

¹H-NMR (500 MHz, MeOD) δ 8.74 (d, 1H), 8.07 (d, 1H), 7.36 (s, 1H),7.29-7.23 (m, 1H), 7.11-7.05 (m, 1H), 7.03 (td, 1H), 6.88 (d, 1H), 6.85(td, 1H), 5.93 (s, 2H), 4.14 (s, 2H), 3.35 (d, 3H), 1.30-1.25 (m, 2H),1.07-1.03 (m, 2H).

Compound I-252

The title compound was prepared following general procedure B, except2-ethyl-2-((methylamino)methyl)butanoic acid (as the TFA salt) was theamine reactant, contents were heated at 100° C. for 20 h, and theaqueous layer during workup was treated with sodium chloride. The crudematerial was purified via silica gel chromatography utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-252 (33 mg, 39%) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.80 (d, 1H), 8.25 (d, 1H), 7.50 (s, 1H),7.32-7.26 (m, 1H), 7.12-7.06 (m, 1H), 7.04 (t, 1H), 6.94 (t, 1H), 6.91(d, 1H), 5.97 (s, 2H), 4.20 (s, 2H), 3.46 (d, 3H), 1.86-1.77 (m, 2H),1.68 (dq, 2H), 0.91 (t, 6H).

Compound I-253

The title compound was prepared following general procedure B, except(S)-3-methyl-2-((methylamino)methyl)butanoic acid (as the TFA salt) wasthe amine reactant, contents were heated at 100° C. for 20 h, and theaqueous layer during workup was treated with sodium chloride. The crudematerial was purified via silica gel chromatography utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-253 (26 mg, 64%) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.74 (d, 1H), 8.08 (d, 1H), 7.37 (s, 1H),7.28-7.22 (m, 1H), 7.10-7.05 (m, 1H), 7.02 (t, 1H), 6.84 (t, 1H), 6.82(d, 1H), 5.97-5.88 (m, 2H), 4.15 (dd, 1H), 3.79 (dd, 1H), 3.32 (d, 3H),2.70-2.64 (m, 1H), 1.93 (dq, 1H), 1.08 (d, 3H), 1.01 (d, 3H).

Compound I-260

The title compound was prepared following general procedure B, except4-benzylpiperidine-4-carboxylic acid was the amine reactant, contentswere heated to 100° C. for 20 h, and the aqueous layer during workup wastreated with sodium chloride. The crude material was purified via silicagel chromatography utilizing a 0-10% methanol/dichloromethane gradientto deliver the desired, Compound I-260 (26 mg, 64%) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.74 (d, 1H), 8.11 (d, 1H), 7.41 (s, 1H),7.29-7.22 (m, 3H), 7.22-7.15 (m, 3H), 7.11-7.06 (m, 1H), 7.05-7.00 (m,1H), 6.91 (d, 1H), 6.84-6.79 (m, 1H), 5.96 (s, 2H), 4.57 (d, 2H),3.29-3.23 (m, 2H), 2.90 (s, 2H), 2.19 (d, 2H), 1.68-1.61 (m, 2H).

Compound I-262

The title compound was prepared following general procedure B, exceptethyl 2-methylpiperidine-2-carboxylate was the amine reactant, contentswere heated to 100° C. for 19 h, and the aqueous layer during workup wastreated with sodium chloride. The crude material was purified viareverse phase HPLC utilizing a 5-75% acetonitrile/water gradient todeliver the desired compound, Compound I-262 (1.1 mg, 8%) as a whitesolid.

¹H-NMR (500 MHz, CD₃OD) δ 8.82 (d, 1H), 8.33 (d, 1H), 7.47 (s, 1H),7.32-7.26 (m, 1H), 7.12-7.07 (m, 1H), 7.05 (t, 1H), 6.92 (t, 1H), 6.88(d, 1H), 6.03-5.95 (m, 2H), 4.32-4.24 (m, 1H), 3.63 (dt, 1H), 2.14 (ddd,1H), 2.01-1.79 (m, 5H), 1.76 (s, 3H).

Compound I-265

The title compound was prepared following general procedure B, except3-phenylpyrrolidine-3-carboxylic acid was the amine reactant, contentswere heated to 100° C. for 24 h, and the aqueous layer during workup wastreated with sodium chloride. The crude material was purified via silicagel chromatography utilizing a 0-10% methanol/dichloromethane gradientto deliver the desired compound, Compound I-265 (29 mg, 45%) as anoff-white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.74 (d, 1H), 8.11 (d, 1H), 7.51-7.44 (m, 3H),7.40-7.36 (m, 2H), 7.32-7.23 (m, 2H), 7.12-7.06 (m, 1H), 7.03 (t, 1H),6.92 (s, 1H), 6.81 (t, 1H), 5.96 (s, 2H), 4.03-3.96 (m, 1H), 3.91 (d,1H), 3.87 (br. s., 1H), 3.07-3.00 (m, 1H), 2.41-2.32 (m, 1H).

Compound I-267

The title compound was prepared following general procedure B, except3,3-dimethylpiperidine-2-carboxylic acid (as the HCl salt) was the aminereactant, contents were heated to 100° C. for 18 h, and the aqueouslayer during workup was treated with sodium chloride. The crude materialwas purified via silica gel chromatography utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-267 (15 mg, 17%) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.81 (d, 1H), 8.35 (d, 1H), 7.57 (s, 1H),7.32-7.26 (m, 1H), 7.12-7.07 (m, 1H), 7.04 (t, 1H), 6.94-6.90 (m, 2H),5.99 (s, 2H), 4.99 (s, 1H), 4.62 (d, 1H), 3.86 (td, 1H), 2.07-1.96 (m,1H), 1.95-1.87 (m, 1H), 1.81-1.75 (m, 1H), 1.50 (d, 1H), 1.22 (s, 3H),1.17 (s, 3H).

Compound I-269

The title compound was prepared following general procedure B, except3-aminobicyclo[1.1.1]pentane-1-carboxylic acid (as the TFA salt) was theamine reactant, contents were heated at 100° C. for 18 h, and theaqueous layer during workup was treated with sodium chloride.

The crude material was purified via silica gel chromatography utilizinga 0-10% methanol/dichloromethane gradient to deliver the desiredcompound, Compound I-269 (11 mg, 16%) as a white solid.

¹H-NMR (500 MHz, CD₃OD δ 8.76 (d, 1H), 8.08 (d, 1H), 7.36 (s, 1H),7.30-7.23 (m, 1H), 7.12-7.06 (m, 1H), 7.04 (t, 1H), 6.96 (d, 1H), 6.91(t, 1H), 5.94 (s, 2H), 2.53 (s, 6H).

Compound I-80

The title compound was prepared following general procedure B, exceptL-phenylalanine was the amine reactant and the contents were heated to90° C. for 48 h as a solution in THF/water (2:1). The contents wereconcentrated in vacuo, and the crude material was purified via reversephase HPLC utilizing a 5-75% acetonitrile/water gradient to deliver thedesired product, Compound I-80 (1.3 mg, 4%) as a white solid.

¹H-NMR (500 MHz, CD₃ODMeOD) δ 8.81 (s, 1H), 8.20 (d, 1H), 7.51-7.48 (m,1H), 7.34-7.26 (m, 3H), 7.22 (t, 2H), 7.17-7.03 (m, 3H), 6.96 (s, 1H),6.90 (t, 1H), 6.00 (s, 2H), 5.36-5.29 (m, 1H), 3.48 (d, 1H), 3.24-3.18(m, 1H).

Compound I-81

The title compound was prepared following general procedure B, exceptL-tryptophan was the amine reactant and the contents were heated at 90°C. for 48 h as a solution in THF/water (2:1). The contents wereconcentrated in vacuo, and the residue was purified via reverse phaseHPLC utilizing a 5-75% acetonitrile/water gradient to deliver thedesired compound, Compound I-81 (7.3 mg, 18%) as a brown solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.86-8.83 (m, 1H), 8.16 (d, 1H), 7.69 (d, 1H),7.33-7.27 (m, 1H), 7.16 (d, 1H), 7.13-7.04 (m, 4H), 7.01-6.96 (m, 1H),6.95-6.88 (m, 3H), 5.96 (s, 2H), 5.51 (dd, 1H), 3.74-3.67 (m, 1H),3.30-3.25 (m, 1H).

Compound I-85

The title compound was prepared following general procedure B, except1-aminocyclopropanecarboxylic acid was the amine reactant and thecontents were heated at 90° C. for 48 h as a solution in THF/water(2:1). The contents were concentrated in vacuo, and the residue waspurified via reverse phase HPLC utilizing a 5-95% acetonitrile/watergradient to deliver the desired compound, Compound I-85 (7.3 mg, 18%) asa clear oil.

¹H-NMR (500 MHz, CD₃OD) δ 8.83 (d, 1H), 8.38 (d, 1H), 7.47 (s, 1H),7.34-7.28 (m, 1H), 7.13-7.04 (m, 2H), 6.99-6.95 (m, 2H), 6.02 (s, 2H),1.84-1.79 (m, 2H), 1.43-1.38 (m, 2H).

Compound I-93

The title compound was prepared following general procedure B, except(3-aminooxetan-3-yl)methanol was the amine reactant and the contentswere heated at 170° C. for 15 min in the microwave as a solution inTHF/water (2:1). The contents were concentrated in vacuo, and theresidue was purified via reverse phase HPLC utilizing a 5-75%acetonitrile/water gradient to deliver the desired compound, CompoundI-93 (0.6 mg, 4%) as a clear oil.

¹H-NMR (500 MHz, CD₃OD) δ 8.85 (d, 1H), 8.55 (s, 1H), 7.69 (s, 1H),7.32-7.37 (m, 1H), 7.09-7.17 (m, 3H), 6.97 (d, 1H), 6.01 (s, 2H), 5.00(s, 2H), 3.76 (q, 4H).

Compound I-102

The title compound was prepared following general procedure B, exceptmethyl 2-amino-2-(oxetan-3-yl)acetate was the amine reactant and thecontents were heated at 100° C. for 42 h as a solution in THF/water(2:1). The contents were concentrated in vacuo, and the residue waspurified via reverse phase HPLC utilizing a 5-75% acetonitrile/watergradient to deliver the desired compound, Compound I-102 (0.6 mg, 2%) asa clear oil.

¹H-NMR (500 MHz, CD₃OD) δ 8.80 (d, 1H), 8.30 (d, 1H), 7.50 (s, 1H),7.32-7.27 (m, 1H), 7.12-7.03 (m, 2H), 6.92 (t, 1H), 6.89 (d, 1H), 5.99(s, 2H), 5.23 (d, 1H), 4.65 (t, 1H), 4.31 (t, 1H), 3.83-3.74 (m, 2H),3.02 (dtd, 1H).

Compound I-109

The title compound was prepared following general procedure B, except noamine reactant was used, DBU was used in place of triethylamine, and thecontents were heated at 100° C. for 18 h as a solution in THF/water(2:1). The contents were concentrated in vacuo, and the residue waspurified via reverse phase HPLC utilizing a 5-75% acetonitrile/watergradient to deliver the desired compound, Compound I-109 (7 mg, 35%) asa clear oil.

¹H-NMR (500 MHz, CD₃OD) δ 8.84 (d, 1H), 8.26 (d, 1H), 7.67 (s, 1H),7.25-7.28 (m, 1H), 7.14-7.05 (m, 2H), 7.02 (d, 1H), 7.01-6.97 (m, 1H),6.03 (s, 2H), 3.79 (t, 2H), 3.56-3.47 (m, 4H), 2.56-2.50 (m, 2H), 1.99(quintet, 2H), 1.80-1.73 (m, 2H), 1.72-1.61 (m, 4H).

Compound I-108

The title compound was prepared following general procedure B, exceptD-tryptophan was the amine reactant and the contents were heated at 100°C. for 18 h as a solution in THF/water (2:1). The contents were treatedwith 3N HCl solution, solvent was removed in vacuo, and the resultingsolid was washed with H₂O, then purified via reverse phase HPLCutilizing a 5-75% acetonitrile/water gradient to deliver the desiredcompound, Compound I-108 (3.5 mg, 16%) as a clear oil.

¹H-NMR (500 MHz, CD₃OD) δ 8.85 (d, 1H), 8.16 (d, 1H), 7.69 (d, 1H),7.33-7.27 (m, 1H), 7.17 (d, 1H), 7.13-7.05 (m, 4H), 7.01-6.96 (m, 1H),6.95-6.89 (m, 3H), 5.97 (s, 2H), 5.50 (dd, 1H), 3.70 (dd, 1H), 3.28 (d,1H).

Compound I-116

The title compound was prepared following general procedure B, exceptD-phenylalanine was the amine reactant and the contents were heated to100° C. for 18 h as a solution in THF/water (2:1). The contents weretreated with 3N HCl solution, solvent was removed in vacuo, and theresulting residue was purified via reverse phase HPLC utilizing a 5-75%acetonitrile/water gradient to deliver the desired compound, CompoundI-116 (25 mg, 61%) as a solid.

¹H-NMR (500 MHz, CD₃OD, MeOD) δ 8.77 (s, 1H), 8.13 (d, 1H), 7.43 (s,1H), 7.31 (d, 2H), 7.28-7.18 (m, 3H), 7.16-7.11 (m, 1H), 7.09-7.03 (m,1H), 7.01 (t, 1H), 6.91 (s, 1H), 6.85 (t, 1H), 5.94 (s, 2H), 5.26 (dd,1H), 3.45 (dd, 1H), 3.19 (dd, 1H).

Compound I-117

The title compound was prepared following general procedure B, exceptL-phenylglycine was the amine reactant and the contents were heated to100° C. for 18 h as a solution in THF/water (2:1). The contents weretreated with 3N HCl solution, solvent was removed in vacuo, and theresulting solid was purified via reverse phase HPLC utilizing a 5-75%acetonitrile/water gradient to deliver the desired compound, CompoundI-117 (26 mg, 63%) as a solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.81 (s, 1H), 8.29 (d, 1H), 7.61 (d, 2H), 7.52(s, 1H), 7.46-7.36 (m, 3H), 7.27 (q, 1H), 7.10-7.05 (m, 1H), 7.03 (t,1H), 6.95-6.90 (m, 2H), 6.02 (s, 1H), 5.97 (s, 2H).

Compound I-118

The title compound was prepared following general procedure B, exceptD-phenylglycine was the amine reactant and the contents were heated to100° C. for 18 h as a solution in THF/water (2:1). The contents weretreated with 3N HCl solution, solvent was removed in vacuo, and theresulting solid was purified via reverse phase HPLC utilizing a 5-75%acetonitrile/water gradient to deliver the desired compound, CompoundI-118 (22 mg, 53%) as a solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.81 (s, 1H), 8.30 (d, 1H), 7.60 (d, 2H), 7.53(s, 1H), 7.46-7.37 (m, 3H), 7.28 (q, 1H), 7.11-7.06 (m, 1H), 7.04 (t,1H), 6.96-6.91 (m, 2H), 6.02 (s, 1H), 5.99 (s, 2H).

Compound I-142

The title compound was prepared following general procedure B, exceptN-methyl phenylglycine was the amine reactant and the contents wereheated to 100° C. for 18 h as a solution in THF/water (2:1). Thecontents were treated with 3N HCl solution, solvent was removed invacuo, and the resulting solid was purified via reverse phase HPLCutilizing a 5-75% acetonitrile/water gradient to deliver the desiredcompound (15 mg, 52%) as a solid.

¹H-NMR (500 MHz, MeOD) δ 8.80 (d, 1H), 8.45-8.39 (m, 1H), 7.58-7.55 (m,1H), 7.50-7.44 (m, 5H), 7.34-7.27 (m, 1H), 7.14-7.04 (m, 2H), 7.00-6.94(m, 1H), 6.90 (d, 1H), 6.61-6.55 (m, 1H), 6.02 (s, 2H), 3.25-3.20 (m,3H).

Compound I-120

The title compound was prepared following general procedure B, except1-(aminomethyl)cyclopropanecarboxylic acid was the amine reactant,contents were heated at 100° C. for 22 h, and the aqueous layer duringworkup was treated with sodium chloride. The crude material was purifiedvia silica gel chromatography utilizing a 0-10% methanol/dichloromethanegradient to deliver the desired compound, Compound I-120 (20 mg, 42%) asa white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.75 (d, 1H), 8.05 (d, 1H), 7.39 (s, 1H),7.30-7.24 (m, 1H), 7.12-7.06 (m, 1H), 7.03 (t, 1H), 6.89 (d, 1H), 6.84(t, 1H), 5.95 (s, 2H), 3.88 (s, 2H), 1.25-1.20 (m, 2H), 1.15-1.10 (m,2H).

Compound I-207

The title compound was prepared following general procedure B, exceptN-methyl-L-alanine was the amine reactant, contents were heated to 100°C. for 22 h, and the aqueous layer during workup was treated with sodiumchloride. The crude material was purified via silica gel chromatographyutilizing a 0-10% methanol/dichloromethane gradient to deliver thedesired compound, Compound I-207 (20 mg, 57%) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.74 (d, 1H), 8.16 (d, 1H), 7.40 (s, 1H),7.29-7.23 (m, 1H), 7.11-7.05 (m, 1H), 7.02 (t, 1H), 6.87 (d, 1H), 6.82(t, 1H), 5.94 (s, 2H), 5.10 (q, 1H), 3.33 (d, 3H), 1.59 (d, 3H).

Compound I-217

The title compound was prepared following general procedure B, except2-(aminomethyl)-2-ethylbutanoic acid was the amine reactant, contentswere heated to 100° C. for 22 h, and the aqueous layer during workup wastreated with sodium chloride. The crude material was purified via silicagel chromatography utilizing a 0-10% methanol/dichloromethane gradientto deliver the desired compound, Compound I-217 (20 mg, 50%) as a clearoil.

¹H-NMR (500 MHz, CD₃OD) δ 8.76-8.72 (m, 1H), 8.07-8.03 (m, 1H),7.42-7.39 (m, 1H), 7.29-7.22 (m, 1H), 7.11-7.04 (m, 1H), 7.02 (t, 1H),6.89-6.81 (m, 2H), 5.94 (s, 2H), 3.91 (s, 2H), 1.68 (q, 4H), 0.98-0.90(t, 6H).

Compound I-224 and Compound I-225

The title compounds were prepared following general procedure B, except2-amino-5,5,5-trifluoro-4-methylpentanoic acid was the amine reactant,contents were heated to 100° C. for 18 h, and the aqueous layer duringworkup was treated with sodium chloride. The crude material was purifiedvia reverse phase HPLC utilizing a 5-75% acetonitrile/water gradient todeliver the desired diastereomers, Compound I-224 (3.3 mg, 7%, elutingfirst on the LCMS) as a white solid and Compound I-225 (2 mg, 5%,eluting second on the LCMS) as a white solid.

¹H-NMR for Compound I-224 (500 MHz, CD₃OD) δ 8.75 (d, 1H), 8.15 (d, 1H),7.38 (s, 1H), 7.29-7.24 (m, 1H), 7.11-7.06 (m, 1H), 7.03 (t, 1H), 6.86(d, 1H), 6.83 (t, 1H), 5.95 (s, 2H), 4.94 (t, 1H), 2.60 (dd, 1H),2.45-2.38 (m, 1H), 1.96-1.89 (m, 1H), 1.25 (d, 3H).

¹H-NMR for Compound I-225 (500 MHz, CD₃OD) δ 8.81 (d, 1H), 8.34 (d, 1H),7.58 (s, 1H), 7.33-7.27 (m, 1H), 7.13-7.08 (m, 1H), 7.06 (t, 1H),6.99-6.92 (m, 2H), 6.01 (s, 2H), 5.26 (dd, 1H), 2.53-2.42 (m, 1H),2.42-2.33 (m, 1H), 2.13 (ddd, 1H), 1.24 (d, 3H).

Compound I-226

The title compound was prepared following general procedure B, except2-amino-3-fluoro-3-methylbutanoic acid was the amine reactant, contentswere heated to 100° C. for 20 h, and the aqueous layer during workup wastreated with sodium chloride. The crude material was purified via silicagel chromatography utilizing a 0-10% methanol/dichloromethane gradientto deliver the desired compound, Compound I-226 (11 mg, 42%) as a whitesolid.

¹H-NMR (500 MHz, CD₃OD) δ 8.75 (d, 1H), 8.16 (d, 1H), 7.44 (s, 1H),7.30-7.22 (m, 1H), 7.11-7.06 (m, 1H), 7.02 (t, 1H), 6.90 (d, 1H), 6.81(t, 1H), 5.95 (s, 2H), 5.13 (d, 1H), 1.65-1.58 (m, 3H), 1.58-1.51 (m,3H).

Compound I-227

The title compound was prepared following general procedure B, except(S)-2-amino-2-cyclopropylacetic acid was the amine reactant, contentswere heated to 100° C. for 20 h, and the aqueous layer during workup wastreated with sodium chloride. The crude material was purified via silicagel chromatography utilizing a 0-10% methanol/dichloromethane gradientto deliver the desired compound, Compound I-227 (21 mg, 86%) as a whitesolid.

¹H-NMR (500 MHz, MeOD) δ 8.74 (d, 1H), 8.10 (d, 1H), 7.37 (s, 1H),7.28-7.22 (m, 1H), 7.11-7.05 (m, 1H), 7.02 (t, 1H), 6.85 (d, 1H), 6.82(t, 1H), 5.93 (s, 2H), 3.96 (d, 1H), 1.38-1.28 (m, 1H), 0.75-0.64 (m,3H), 0.53-0.47 (m, 1H).

Compound I-239

The title compound was prepared following general procedure B, except(S)—N-methyl-2-amino-2-cyclopropylacetic acid was the amine reactant,contents were heated to 100° C. for 20 h, and the aqueous layer duringworkup was treated with sodium chloride. The crude material was purifiedvia silica gel chromatography utilizing a 0-10% methanol/dichloromethanegradient to deliver the desired compound, Compound I-239 (4 mg, 20%) asa white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.75 (d, 1H), 8.16 (d, 1H), 7.39 (s, 1H), 7.26(ddd, 1H), 7.08 (ddd, 1H), 7.04-7.00 (m, 1H), 6.86 (d, 1H), 6.82 (td,1H), 5.94 (s, 2H), 4.19 (d, 1H), 3.48 (d, 3H), 1.53-1.44 (m, 1H),0.91-0.83 (m, 1H), 0.76-0.64 (m, 2H), 0.44 (dq, 1H).

Compound I-240

The title compound was prepared following general procedure B, except(R)-2-amino-2-cyclopropylacetic acid was the amine reactant, contentswere heated to 100° C. for 2 h, and the aqueous layer during workup wastreated with sodium chloride. The crude material was purified via silicagel chromatography utilizing a 0-10% methanol/dichloromethane gradientto deliver the desired compound, Compound I-240 (46 mg, 93%) as a whitesolid.

¹H-NMR (500 MHz, CD₃OD) δ 8.74 (d, 1H), 8.10 (d, 1H), 7.36 (s, 1H),7.28-7.22 (m, 1H), 7.07 (ddd, 1H), 7.01 (td, 1H), 6.84 (d, 1H), 6.81(td, 1H), 5.93 (s, 2H), 3.96 (d, 1H), 1.38-1.30 (m, 1H), 0.74-0.65 (m,3H), 0.52-0.47 (m, 1H).

Compound I-241

The title compound was prepared following general procedure B, except(R)—N-methyl-2-amino-2-cyclopropylacetic acid (as the TFA salt) was theamine reactant, contents were heated to 100° C. for 20 h, and theaqueous layer during workup was treated with sodium chloride. The crudematerial was purified via silica gel chromatography utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-241 (20 mg, 93%) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.74 (d, 1H), 8.15 (d, 1H), 7.38 (s, 1H),7.28-7.22 (m, 1H), 7.10-7.04 (m, 1H), 7.04-6.99 (m, 1H), 6.85 (d, 1H),6.82 (t, 1H), 5.93 (s, 2H), 4.18 (d, 1H), 3.48 (d, 3H), 1.53-1.44 (m,1H), 0.91-0.82 (m, 1H), 0.76-0.64 (m, 2H), 0.48-0.41 (m, 1H).

Compound I-90

The title compound was prepared following general procedure B, except(S)-indoline-2-carboxylic acid was the amine reactant (1 equiv.), andthe contents were heated at 90° C. for 12 h as a solution in THF/water(1:1), followed by heating at 125° C. for 15 min in the microwave. Thecontents extracted with ethyl acetate during workup. The crude materialwas purified via by reverse phase HPLC using 5 to 95% acetonitrile inwater spiked with 0.1% trifluoroacetic acid to afford the desiredcompound, Compound I-90 (3.9 mg, 15% yield) as an off-white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ (ppm): 9.10-9.21 (d, 1H), 8.61-8.75 (m, 1H),8.47-8.57 (d, 1H), 7.49-7.58 (s, 1H), 7.33-7.41 (m, 1H), 7.22-7.33 (m,4H), 7.10-7.20 (m, 2H), 6.98-7.10 (m, 1H), 5.95 (s, 2H), 5.39-5.53 (m,1H), 3.64-3.74 (dd, 1H), 3.20-3.32 (dd, 2H).

Compound I-91

The title compound was prepared following general procedure B, except(R)-indoline-2-carboxylic acid was the amine reactant (1 equiv.), andthe contents were heated to 90° C. for 12 h as a solution in THF/water(1:1), followed by heating at 125° C. for 15 min in the microwave.Contents extracted with ethyl acetate during workup. The crude materialwas purified via reverse phase HPLC using a 5-95% acetonitrile in watergradient (in 0.1% TFA) to deliver the desired compound, Compound I-91Compound obtained following usual procedure (1.9 mg, 7%).

¹H NMR (500 MHz, CD₃CN) δ (ppm): 8.68-8.75 (d, 1H), 8.35-8.49 (m, 2H),7.42-7.49 (m, 1H), 7.27-7.41 (m, 3H), 7.05-7.24 (m, 4H), 6.91-6.96 (m,1H), 5.97 (s, 2H), 5.38-5.48 (m, 1H), 3.65-3.79 (dd, 1H), 3.31-3.44 (dd,1H).

Compound I-114

Purification was achieved by reverse phase HPLC using 5-75% acetonitrilein water over 30 minutes (spiked with 0.1% trifluoroacetic acid) toafford the desired compound (1.6 mg, 4% yield) as a clear oil. Only thelater running diastereomer (Compound I-114) was purified from thisreaction mixture.

¹H NMR (500 MHz, 500 MHz, CD₃CN) δ (ppm): 8.85 (s, 1H), 8.33 (d, 1H),7.40-7.48 (m, 1H), 7.28-7.38 (m, 1H), 7.04-7.19 (m, 2H), 6.90-7.00 (m,2H), 6.03 (s, 2H), 3.13-3.17 (m, 1H), 2.47-2.59 (m, 1H), 2.36-2.42 (m,1H), 2.03-2.17 (m, 1H), 1.77-1.85 (m, 1H), 1.65-1.74 (m, 2H), 1.49-1.60(m, 2H), 1.38-1.47 (m, 1H).

Compound I-107

The title compound was prepared following general procedure B, except(1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid was the aminereactant (1 equiv.), 3 equivalents of triethyl amine was used, and thecontents were heated to 70° C. for 14 h as a solution in THF/water(10:1). Contents extracted with ethyl acetate during workup, dried,filtered, and concentrated to deliver the desired compound. CompoundI-107 (38.3 mg, 100% yield) was obtained as a light-tan solid. Nopurification was necessary for this compound.

¹H NMR (500 MHz, CD₃OD) δ ppm: 8.79 (s, 1H), 8.23 (d, 1H), 7.36-7.46(br. s, 1H), 7.25-7.31 (m, 1H), 7.06-7.12 (m, 1H), 7.01-7.06 (m, 1H),6.83-6.90 (m, 2H, 2 shifts overlapping), 5.96 (s, 2H), 4.18 (dd, 1H),4.02-4.08 (m, 1H), 1.93-2.02 (m, 1H), 0.83-0.93 (m, 4H).

Compound I-129

Purification was achieved by silica gel chromatography using 1 to 10%methanol in dichloromethane over 30 minutes to afford Compound I-129(21.7 mg, 57% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.45-8.57 (m, 2H, 2 shifts isochronous)7.40-7.48 (m, 3H), 7.24-7.40 (m, 1H), 6.93-7.09 (m, 2H), 6.58-6.68 (m,1H), 5.90 (s, 2H), 3.74-3.90 (m, 2H), 1.99-2.20 (m, 2H), 1.70-1.89 (m,4H), 1.55-1.69 (m, 2H).

Compound I-124

The title compound was prepared following general procedure B, except4-methylpiperidine-4-carboxylic acid (as the HCl salt) was the aminereactant (1.1 equiv.), 4 equivalents of triethyl amine was used, and thecontents were heated to 80° C. for 18 h as a solution in THF/water(10:1). Contents extracted with ethyl acetate during workup. The crudematerial was purified via silica gel chromatography utilizing a 1-10%methanol/dichloromethane gradient over 30 minutes to deliver the desiredcompound, Compound I-124 as an off-white solid (36.1 mg, 95% yield).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.49 (s, 1H), 8.16-8.28 (d, 1H),7.35-7.44 (m, 1H), 7.17-7.26 (m, 1H), 6.95-7.10 (m, 2H), 6.87 (m, 1H),6.62 (s, 1H), 6.00 (s, 2H), 4.34-4.48 (m, 1H), 3.36-3.48 (m, 1H),2.36-2.41 (m, 1H), 1.58-1.68 (m, 1H), 1.34 (s, 3H), 0.71-0.81 (m, 4H).

Compound I-143

The title compound was prepared following general procedure B, except3-methylpyrrolidine-3-carboxylic acid was the amine reactant (1.05equiv.), 4 equivalents of triethyl amine was used, and the contents wereheated to 80° C. for 4 h as a solution in THF/water (10:1). Contentsextracted with ethyl acetate during workup. The crude material waspurified via silica gel chromatography utilizing a 1-10%methanol/dichloromethane gradient over 30 minutes to deliver the desiredcompound, Compound I-143 as a white solid (18.9 mg, 48% yield).

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.45 (s, 1H), 8.12-8.19 (d, 1H), 7.30(s, 1H), 7.27 (s, 1H), 7.14-7.22 (m, 1H), 6.98-7.05 (m, 1H), 6.93-6.98(m, 1H), 6.80-6.87 (m, 1H), 6.57 (d, 1H), 5.96 (s, 2H), 4.24-4.36 (m,1H), 3.84-4.00 (m, 2H), 3.59-3.70 (m, 1H), 2.45-2.58 (m, 1H), 1.84-2.00(m, 1H), 1.47 (s, 3H).

Compound I-152

The title compound was prepared following general procedure B, except4,4-Dimethyl-pyrrolidine-3-carboxylic acid was the amine reactant (1.05equiv.), 4 equivalents of triethyl amine was used, and the contents wereheated to 90° C. for 14 h as a solution in THF/water (10:1). Contentsextracted with ethyl acetate during workup. The crude material waspurified via silica gel chromatography utilizing a 1-7%methanol/dichloromethane gradient over 30 minutes to deliver the desiredcompound, Compound I-152 as an off-white solid (14.3 mg, 37% yield).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.45 (s, 1H), 8.05-8.20 (d, 1H),7.29-7.34 (m, 1H), 7.14-7.25 (m, 1H), 6.91-7.08 (m, 2H), 6.79-6.87 (m,1H), 6.56-6.63 (m, 1H), 5.96 (s, 2H), 4.01-4.23 (m, 2H), 3.71-3.87 (dd,1H), 3.53-3.65 (dd, 1H), 2.85-2.97 (m, 1H), 1.34 (s, 3H), 1.15 (s, 3H).

Compound I-186

The title compound was prepared following general procedure B, except4-phenylpiperidine-4-carboxylic acid (as the HCl salt) was the aminereactant (1.05 equiv.), 4 equivalents of triethyl amine was used, andthe contents were heated to 70° C. for 24 h as a solution in THF/water(10:1). Contents extracted with ethyl acetate during workup. The crudematerial was purified via silica gel chromatography utilizing a 4-7%methanol/dichloromethane gradient over 40 minutes to deliver the desiredcompound, Compound I-186 as a white solid (22.3 mg, 51% yield).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.46 (s, 1H), 8.19 (d, 1H), 7.44-7.49(m, 2H, 2 shifts overlapping), 7.36-7.41 (m, 2H), 7.29-7.34 (m, 2H),7.16-7.22 (m, 2H), 6.99-7.05 (m, 1H), 6.93-6.98 (m, 1H), 6.81-6.86 (m,1H), 6.59 (m, 1H), 5.97 (s, 2H), 4.50-4.58 (m, 2H), 3.42-3.50 (m, 2H),2.69-2.75 (m, 2H), 2.07-2.14 (m, 2H).

Compound I-194

This compound was prepared following the general procedure B describedabove, except 4-(aminomethyl)tetrahydro-2H-pyran-4-carboxylic acid wasthe amine reactant (1.05 equiv.), 4 equivalents of triethyl amine wasused, and the contents were heated at 70° C. for 6 h as a solution inTHF/water (10:1), followed by heating at 90° C. for 12 h. Contentsextracted with ethyl acetate during workup. and purification wasachieved by silica gel chromatography using 4 to 7% methanol indichloromethane over 40 minutes to deliver the desired compound,Compound I-194 ((26.8 mg, 66% yield) as a white solid

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.46 (s, 1H), 8.10 (d, 1H), 7.28 (s,1H), 7.18-7.24 (m, 1H), 6.94-7.07 (m, 3H), 6.58 (d, 1H), 5.95 (s, 2H),5.50-5.57 (m, 1H), 3.86-3.94 (m, 2H), 3.79-3.85 (m, 2H), 3.51-3.60 (m,2H), 2.12-2.20 (m, 2H), 1.53-1.62 (m, 2H).

Compound I-228

The title compound was prepared in 4 steps: Step 1:1-((4-methylphenylsulfonamido)methyl)cyclopentanecarboxylic acid

A slurry of 1-(aminomethyl)cyclopentanecarboxylic acid (316 mg, 1.0equiv.), p-toluenesulfonyl chloride (505 mg, 1.2 equiv) and 1M aqueoussodium hydroxide solution (6.62 mL, 3.0 equiv.) was heated in water (10mL) at 90° C. for 1 hour, after which the reaction mixture was cooled to0° C. and acidified by the addition of 3M aqueous hydrochloric acidsolution. The resulting white precipitate was filtered then washedsuccessively with water and ethanol to afford1-((4-methylphenylsulfonamido)methyl)cyclopentanecarboxylic acid (383mg, 58% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ (ppm): 12.14-12.38 (s, 1H), 7.64-7.75 (d,2H), 7.47-7.56 (t, 1H), 7.33-7.45 (d, 2H), 2.79-2.90 (d, 2H), 2.38 (s,3H), 1.81-1.95 (m, 2H), 1.47-1.65 (m, 6H).

Step 2: 1-((N,4-dimethylphenylsulfonamido)methyl)cyclopentanecarboxylicacid

A solution of1-((4-methylphenylsulfonamido)methyl)cyclopentanecarboxylic acid (383mg, 1.0 equiv.), iodomethane (0.254 mL, 3.15 equiv.), and 1M aqueoussodium hydroxide solution (5.15 mL, 4.0 equiv.) in water (5 mL) washeated to 75° C. for 1.5 hours, after which LCMS analysis indicated thatthe reaction was complete. The reaction mixture was cooled to roomtemperature, washed with dichloromethane (3×30 mL), acidified by theaddition of 3M aqueous hydrochloric acid solution, extracted withdiethyl ether (3×30 mL), dried (sodium sulfate), filtered, andconcentrated to afford1-((N,4-dimethylphenylsulfonamido)methyl)cyclopentanecarboxylic acid(343 mg, 86% yield) as a yellow-gold solid. No purification wasnecessary.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.59-7.73 (d, 2H), 7.30-7.41 (d, 2H),3.24-3.39 (s, 2H), 2.71 (s, 3H), 2.45 (s, 3H), 2.06-2.22 (m, 2H),1.69-1.88 (m, 6H).

Step 3: 1-((methylamino)methyl)cyclopentanecarboxylic acid hydrobromide

A solution of1-((N,4-dimethylphenylsulfonamido)methyl)cyclopentanecarboxylic acid(343 mg, 1.0 equiv.) was heated in a 33% glacial acetic acid solution ofhydrogen bromide (6.0 mL, 30 equiv.) for 2 hours at 75° C. The reactionwas then cooled to room temperature, diluted in water (10 mL), andwashed with diethyl ether (3×40 mL). The aqueous layer was concentratedto dryness and the resulting solid was recrystallized in acetone toafford 1-((methylamino)methyl)cyclopentanecarboxylic acid hydrobromide(127 mg, 48% yield) as a crystalline white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ (ppm): 12.76-13.15 (s, 1H), 8.12-8.39 (m,2H), 2.98-3.11 (m, 2H), 2.55 (s, 3H), 1.86-2.01 (m, 2H), 1.62 (m, 6H).

Step 4: compound I-228

The title compound was prepared following general procedure B, except1-((methylamino)methyl)cyclopentanecarboxylic acid (as the HBr salt) wasthe amine reactant (1.3 equiv.), 4 equivalents of triethyl amine wasused, and the contents were heated at 90° C. for 6 h as a solution inTHF/water (10:1). Contents were extracted with ethyl acetate duringworkup. Purification was achieved by silica gel chromatography using 2to 5% methanol in dichloromethane over 40 minutes. The desired compoundwas obtained as a white solid (13.4 mg, 45% yield).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.44 (s, 1H), 8.08 (d, 1H), 7.29 (s,1H), 7.15-7.25 (m, 1H), 6.95-7.08 (m, 3H), 6.55-6.58 (m, 1H), 5.95 (s,2H), 4.02 (s, 2H), 3.35 (d, 3H), 2.18-2.29 (m, 2H), 1.57-1.79 (m, 6H).

Compound I-238

The title compound was prepared in 4 steps:

Step 1:4-((4-methylphenylsulfonamido)methyl)tetrahydro-2H-pyran-4-carboxylicacid

A slurry of 4-(aminomethyl)tetrahydro-2H-pyran-4-carboxylic acid (500mg, 1.0 equiv.), p-toluenesulfonyl chloride (719 mg, 1.2 equiv.) and 1Maqueous sodium hydroxide solution (9.4 mL, 3.0 equiv.) was heated at 90°C. for 1 hour after which the reaction mixture was cooled to 0° C. andacidified by the addition of 3M aqueous hydrochloric acid solution. Theresulting white precipitate was filtered then washed successively withwater and ethanol to afford4-((4-methylphenylsulfonamido)methyl)tetrahydro-2H-pyran-4-carboxylicacid (840 mg, 85% yield) as a white solid. No purification wasnecessary.

¹H-NMR (400 MHz, DMSO-d₆) δ (ppm): 12.6 (br. s, 1H), 7.68 (d, 2H), 7.66(t, 1H), 7.39 (d, 2H), 3.63-3.72 (m, 2H), 3.27-3.32 (m, 2H), 2.81 (d,2H), 2.38 (s, 3H), 1.76-1.85 (m, 2H), 1.33-1.46 (m, 2H).

Step 2:4-((N,4-dimethylphenylsulfonamido)methyl)tetrahydro-2H-pyran-4-carboxylicacid

A suspension of4-((4-methylphenylsulfonamido)methyl)tetrahydro-2H-pyran-4-carboxylicacid (840 mg, 1.0 equiv.) in 1M aqueous sodium hydroxide solution (10.7mL, 4.0 equiv.) and iodomethane (0.528 mL, 3.15 equiv.) was heated to100° C. for two hours after which the reaction mixture was diluted in 3Maqueous hydrochloric acid solution, extracted with dichloromethane (3×30mL), dried (sodium sulfate), filtered and concentrated to afford4-((N,4-dimethylphenylsulfonamido)methyl)tetrahydro-2H-pyran-4-carboxylicacid (197 mg, 22% yield) as a creme-colored solid. No purification wasnecessary.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.63-7.72 (d, 2H), 7.31-7.39 (d, 2H),3.87-3.97 (m, 2H), 3.50-3.61 (m, 2H), 3.25 (s, 2H), 2.76 (s, 3H), 2.45(s, 3H), 2.13-2.23 (m, 2H), 1.62-1.74 (m, 2H).

Step 3: 4-((methylamino)methyl)tetrahydro-2H-pyran-4-carboxylic acidhydrobromide

A solution of4-((N,4-dimethylphenylsulfonamido)methyl)tetrahydro-2H-pyran-4-carboxylicacid (197 mg, 1.0 equiv.) was heated in a 33% glacial acetic acidsolution of hydrogen bromide (1 mL, 31 equiv.) at 85° C. for 3 hours,after which LCMS analysis indicated that the starting material had beenconsumed. After cooling the reaction mixture to room temperature, waterwas added, and the reaction mixture was washed with diethyl ether (3×30mL). The water layer was concentrated to dryness, and the resultingsolid was recrystallized from acetone to afford4-((methylamino)methyl)tetrahydro-2H-pyran-4-carboxylic acidhydrobromide (54.8 mg, 36% yield) as a white solid.

¹H NMR (500 MHz, D₂O) δ (ppm): 3.71-3.89 (m, 2H), 3.50-3.64 (m, 2H),3.17 (s, 2H), 2.66 (s, 3H), 1.96-2.09 (m, 2H), 1.48-1.66 (m, 2H).

Step 4: Compound I-238

This compound was prepared following general procedure B, with theexception that 4-((methylamino)methyl)tetrahydro-2H-pyran-4-carboxylicacid (as the HBr salt) was the amine reactant (1.05 equiv.), 4equivalents of triethyl amine was used, and the reaction was conductedin dioxane/water (3:1) at 90° C. for 18 hours. Contents extracted withethyl acetate during workup. and the purification was achieved by silicagel chromatography using 2 to 7% methanol in dichloromethane over 40minutes to deliver the desired compound, Compound I-238, as a whitesolid (31.0 mg, 43% yield) following the procedure described for above.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.47 (s, 1H), 8.06 (d, 1H), 7.31 (s,1H), 7.23-7.27 (m, 1H), 7.22 (br. s, 1H), 7.00-7.09 (m, 3H), 6.59 (d,1H), 5.96 (s, 2H), 3.83-3.95 (m, 4H), 3.47-3.56 (m, 2H), 3.40 (d, 3H),2.20-2.26 (m, 2H), 1.51-1.64 (m, 2H).

Compound I-244

The title compound was prepared in 4 steps:

Step 1: 4,4,4-trifluoro-2-(4-methylphenylsulfonamido)butanoic acid

A slurry of 2-amino-4,4,4-trifluorobutanoic acid (300 mg, 1.0 equiv.),p-toluenesulfonyl chloride (437 mg, 1.2 equiv.) and 1M aqueous sodiumhydroxide solution (5.73 ml, 3.0 equiv.) was heated in water (4 mL) at90° C. for 1 hour, after the reaction mixture was cooled to 0° C., andacidified by the addition of 3M aqueous hydrochloric acid solution,extracted with dichloromethane (3×40 mL), dried (sodium sulfate),filtered and concentrated to afford4,4,4-trifluoro-2-(4-methylphenylsulfonamido)butanoic acid (175 mg, 29%yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.71-7.80 (d, 2H), 7.28 (d, 2H,isochronous with chloroform), 5.72-5.91 (br. s, 1H), 4.16-4.29 (m, 1H),2.64-2.76 (m, 1H), 2.52-2.63 (m, 1H), 2.43 (s, 3H).

Step 2: 2-(N, 4-dimethylphenylsulfonamido)-4,4,4-trifluorobutanoic acid

A mixture of 4,4,4-trifluoro-2-(4-methylphenylsulfonamido)butanoic acid(175 mg, 1.0 equiv.) and iodomethane (146 μL, 3.15 equiv.) in 1M aqueoussodium hydroxide solution (2.81 mL, 4.0 equiv.) was heated at 85° C. for2.5 hour after which LCMS analysis indicated the presence of the desiredproduct and the methyl ester of the desired product. The reactionmixture was acidified with 3M hydrochloric acid solution, extracted withdichloromethane (3×30 mL), dried (sodium sulfate), filtered andconcentrated to a residue. This residue was reconstituted intetrahydrofuran (2 mL), then treated with 1M aqueous sodium hydroxidesolution (0.5 mL). After 30 minutes of stirring at room temperature, thereaction mixture was acidified with 3M hydrochloric acid solution,extracted with dichloromethane (3×30 mL), dried (sodium sulfate), andconcentrated to afford2-(N,4-dimethylphenylsulfonamido)-4,4,4-trifluorobutanoic acid (66 mg,36% yield) as a gum with about 90% purity by ¹H NMR. Used as is in thenext step without further purification.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.60-7.70 (d, 2H), 7.19 (d, 2H),4.90-4.99 (m, 1H), 2.75-2.89 (m, 1H), 2.66-2.72 (s, 3H), 2.30-2.44 (m,1H), 2.29 (s, 3H).

Step 3: 4,4,4-trifluoro-2-(methylamino)butanoic acid hydrobromide

A solution of 2-(N,4-dimethylphenylsulfonamido)-4,4,4-trifluorobutanoicacid (66 mg, 1.0 equiv.) in a 33% glacial acetic acid solution ofhydrogen bromide (1.0 mL, 91 equiv.) was heated to 85° C. for 2 hours.Starting material still remained. Allowed to stir at 60° C. for 72 hoursafter which the deprotection was nearly complete. The reaction mixturewas diluted in water, washed with diethyl ether (3×30 mL), and the waterlayer was concentrated to dryness. This crude material was used as is inthe next step without any purification.

Step 4: Compound I-244

This compound was prepared following the procedure B described abovewith the exception that 4,4,4-trifluoro-2-(methylamino)butanoic acid (asthe HBr salt) was the amine reactant (1.2 equiv.), 4 equivalents oftriethyl amine was used and the reaction was conducted in dioxane/water(3:1) at 90° C. for 5 days. The crude material was purified via silicagel chromatography utilizing a 2-10% methanol/dichloromethane gradientover 40 minutes to deliver the desired compound, Compound I-244 (24.7mg, 32% yield) as a tan solid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.77 (s, 1H), 8.21 (d, 1H), 7.41 (m,1H), 7.24-7.33 (m, 1H), 6.07-7.13 (m, 1H), 7.02-7.07 (m, 1H), 6.90 (d,1H), 6.82-6.88 (m, 1H), 5.97 (s, 2H), 3.38-3.46 (m, 2H), 3.33-3.36 (m,1H), 3.03-3.19 (m, 3H).

Compound I-94

Compound was prepared following general procedure B, with the exceptionthat methyl 1-aminocyclobutanecarboxylate was the amine reactant, 5equivalents of triethylamine was used, the reaction was heated at 90° C.as a solution in THF/water (10:1) for 14 h, followed by heating at 170°C. for 10 minutes in the microwave. The contents were then treated withwater and solid 1N HCl and dried in vacuo. The crude material waspurified via preparative reverse-phase HPLC to afford the desiredcompound, Compound I-94 (0.30 mg, 1.5% yield) as a white solid.

¹H NMR (500 MHz, METHANOL-d4) δ (ppm): 8.81 (d, 1H), 8.23 (d, 1H), 7.34(s, 1H), 7.25-7.31 (m, 1H), 7.01-7.13 (m, 2H), 6.86-6.94 (m, 2H), 5.97(s, 2H), 2.89 (ddd, 2H), 2.45-2.54 (m, 2H), 2.07-2.14 (m, 1H), 1.95-2.03(m, 1H).

Compound I-138

This compound was prepared as above with the exception that methyl1-aminocyclopentanecarboxylate (as the HCl salt) was the amine reactant,the mixture was heated for 5 hours at 140° C. in DMA (Volume: 142 μl) togive the ester. The reaction then allowed to stir at room temperature(23° C.) for 16 hrs. Sodium hydroxide (14.2 mg) was added and reactionand heated at 40 for 1 hr, then cooled, water added, reactionneutralized with 1N HCl and extracted with ethyl acetate (3 times). Theorganics were combined and dried, purified via reverse phase preparativeHPLC to afford the desired compound, Compound I-138 (0.5 mg, 1.5%yield).

¹H NMR (500 MHz, METHANOL-d4) δ (ppm): 8.84 (s, 1H), 8.29 (d, 1H), 7.40(s, 1H), 7.28-7.35 (m, 1H), 7.04-7.16 (m, 2H), 6.91-7.00 (m, 2H), 6.01(s, 2H), 2.50-2.62 (m, 3H), 2.17-2.26 (m, 2H), 1.90 (br. s., 3H).

Compound I-156

A mixture of Intermediate 1 (30.8 mg),(1S,2R)-2-aminocyclopentanecarboxylic acid (31.9 mg, 3 equiv.) andtriethylamine (115 μl, 10 equiv.) were heated to 80° C. for 16 hours ina 10:1 mixture of THF/Water. Contents were concentrated in vacuo, andpurified via Preparative reverse-phase HPLC to afford the desiredcompound, Compound I-156, as a white solid (6.2 mg, 16% yield).

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.52 (s, 1H), 8.46 (br. s., 1H), 7.44(br. s., 2H), 7.22-7.27 (m, 1H), 7.15 (t, 1H), 7.00-7.09 (m, 2H), 6.66(s, 1H), 5.94 (s, 2H), 4.88 (br. s., 1H), 3.13-3.21 (m, 1H), 2.23 (d,1H), 2.15 (br. s., 2H), 1.85-2.03 (m, 2H), 1.76 (d, 1H).

Compound I-154

The title compound was prepared following general procedure B, exceptcis-2-aminocyclohexanecarboxylic acid was the amine reactant and themixture was heated at 80° C. for 24 h as a solution in THF/water (10:1).Contents were concentrated in vacuo, and purified via reverse phase HPLCto deliver the desired compound, Compound I-154 (8.5 mg, 26% yield) as awhite solid.

¹H NMR (500 MHz, CDCl₃) δ ppm: 8.62 (d, 1H), 8.53 (d, 1H), 7.79 (br. s.,1H), 7.45 (s, 1H), 7.19-7.27 (m, 2H), 7.00-7.10 (m, 2H), 6.67 (s, 1H),5.94 (s, 2H), 4.58 (br. s., 1H), 2.94 (d, 1H), 2.33 (d, 1H), 1.87 (br.s., 2H), 1.81 (d, 1H), 1.61-1.74 (m, 2H), 1.36-1.57 (m, 2H).

Compound I-159

The title compound was prepared following general procedure B, except3-(4-Hydroxyphenyl)-L-alanine was the amine reactant and the mixture washeated at 80° C. for 18 h as a solution in THF/water (10:1). Contentswere concentrated in vacuo, and purified via reverse phase HPLC todeliver the desired compound, Compound I-159 as a brown oil.

¹H NMR (500 MHz, CD₃OD) δ ppm: 8.82 (d, 1H), 8.22 (d, 1H), 7.52 (s, 1H),7.25-7.33 (m, 1H), 7.02-7.15 (m, 4H), 6.97 (d, 1H), 6.92 (t, 1H), 6.64(d, 2H), 6.00 (s, 2H), 5.29 (dd, 1H), 3.40 (dd, 1H), 3.09 (dd, 1H).

Compound I-165

The title compound was prepared following general procedure B, except3-(4-Hydroxyphenyl)-D-alanine was the amine reactant and the mixture washeated at 80° C. for 90 h as a solution in THF/water (10:1). Contentswere concentrated in vacuo, and purified via reverse phase HPLC todeliver the desired compound, Compound I-165 (4.7 mg, 13% yield) as abrown oil.

¹H NMR (500 MHz, CD₃OD) δ ppm: 8.82 (d, 1H), 8.24 (d, 1H), 7.53 (s, 1H),7.26-7.38 (m, 1H), 7.13 (d, 2H), 7.04-7.11 (m, 2H), 6.98 (d, 1H), 6.93(t, 1H), 6.64 (d, 2H), 6.01 (s, 2H), 5.30 (dd, 1H), 3.41 (dd, 1H), 3.09(dd, 1H).

Compound I-179

The title compound was prepared following general procedure B, except(1S,3R)-3-aminocyclopentanecarboxylic acid was the amine reactant andthe mixture was heated at 80° C. for 48 h as a solution in THF/water(10:1). Contents were concentrated in vacuo, and purified via reversephase HPLC to deliver the desired compound, Compound I-179 (1.7 mg, 5%yield).

¹H NMR (400 MHz, CD₃OD) δ ppm: 8.83 (d, 1H), 8.23 (d, 1H), 7.67 (s, 1H),7.26-7.35 (m, 1H), 7.12 (d, 1H), 7.05-7.10 (m, 1H), 7.01 (d, 1H),6.94-7.00 (m, 1H), 6.03 (s, 2H), 2.96-3.06 (m, 1H), 2.42-2.54 (m, 1H),2.21 (td, 1H), 1.97-2.15 (m, 4H), 1.80-1.96 (m, 1H).

Compound I-188

The title compound was prepared following general procedure B, except4-Fluoro-4-piperidinecarboxylic acid (as the HCl salt) was the aminereactant and the mixture was heated at 80° C. for 8 h as a solution inTHF/water (10:1) followed by stirring at 23° C. for an additional 8 h.Contents were concentrated in vacuo, and purified via reverse phase HPLCto deliver the desired compound, Compound I-188 (7 mg, 18% yield) as awhite solid.

¹H NMR (500 MHz, CD₃OD) δ ppm: 8.81 (d, 1H), 8.32 (d, 1H), 7.63 (s, 1H),7.26-7.33 (m, 1H), 7.03-7.14 (m, 2H), 6.91-6.98 (m, 2H), 6.01 (s, 2H),4.82 (br. s., 1H), 3.59-3.73 (m, 2H), 2.26-2.41 (m, 2H), 2.16-2.23 (m,2H), 0.10 (m, 1H).

Compound I-199

The title compound was prepared following general procedure B, except(S)-2-Amino-4-(methylmercapto)butyric acid was the amine reactant andthe mixture was heated at 80° C. for 16 h as a solution in THF/water(10:1). Contents were concentrated in vacuo, and purified via reversephase HPLC to deliver the desired compound, Compound I-199 (4 mg, 9%yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm: 8.82 (d, 1H), 8.34 (d, 1H), 7.58 (s, 1H),7.27-7.34 (m, 1H), 7.04-7.14 (m, 2H), 6.93-7.00 (m, 2H), 6.02 (s, 2H),5.24 (dd, 1H), 2.59-2.79 (m, 2H), 2.36-2.46 (m, 1H), 2.22-2.31 (m, 1H),2.12 (s, 3H).

Compound I-192

The title compound was prepared following general procedure B, except3-(Methanesulfonyl)pyrrolidine was the amine reactant and the mixturewas heated at 80° C. for 48 h as a solution in THF/water (10:1).Contents acidified with 1N hydrochloric acid, concentrated in vacuo, andpurified via reverse phase HPLC to deliver the desired compound,Compound I-192 (6.3 mg, 18% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm: 8.81 (d, 1H), 8.30 (d, 1H), 7.61 (s, 1H),7.30 (ddd, 1H), 7.03-7.14 (m, 2H), 6.88-6.98 (m, 2H), 6.01 (s, 2H),4.41-4.54 (m, 1H), 4.27-4.38 (m, 1H), 4.06-4.27 (m, 3H), 3.11 (s, 3H),2.52-2.68 (m, 2H).

Compound I-220

The title compound was prepared following general procedure B, exceptβ-cyano-L-alanine was the amine reactant and the mixture was heated at80° C. for 18 h as a solution in THF/water (10:1). Contents concentratedin vacuo, and purified via reverse phase HPLC to deliver the desiredcompound, Compound I-220 (2.5 mg, 8% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm: 8.79 (d, 1H), 8.30 (d, 1H), 7.52 (s, 1H),7.25-7.31 (m, 1H), 7.02-7.13 (m, 2H), 6.86-6.95 (m, 2H), 5.99 (s, 2H),5.34 (dd, 1H), 3.15-3.25 (m, 2H).

Compound I-198

The title compound was prepared following general procedure B, excepttrans-2-aminocyclohexanecarboxylic acid was the amine reactant and themixture was heated at 80° C. for 16 h as a solution in THF/water (10:1).Contents acidified with 1N hydrochloric acid solution, and the solidswere filtered, re-suspended in dichloromethane, and filtered to deliverthe desired compound, Compound I-198 (14.5 mg, 31% yield) as a whitesolid.

¹H NMR (500 MHz, METHANOL-d4) 8 ppm: 8.75 (d, 1H), 8.00 (d, 1H), 7.42(s, 1H), 7.23-7.29 (m, 1H), 7.05-7.11 (m, 1H), 7.02 (t, 1H), 6.89-6.92(m, 1H), 6.81 (t, 1H), 5.95 (s, 2H), 4.58 (td, 1H), 2.56 (td, 1H),1.98-2.14 (m, 2H), 1.78-1.90 (m, 2H), 1.67 (qd, 1H), 1.48-1.61 (m, 1H),1.28-1.47 (m, 2H).

Compound I-208

The title compound was prepared following general procedure B, exceptoctahydrocyclopenta[c]pyrrole-3a-carboxylic acid (4 equiv.) was theamine reactant and the mixture was heated at 80° C. for 5 h as asolution in THF/water (10:1). Contents were blown dry with nitrogen, andthe crude mixture was re-suspended in methanol and filtered to deliverthe desired compound, Compound I-208 (37 mg, 93% yield).

¹H NMR (500 MHz, METHANOL-d4) 6 ppm: 8.74 (d, 1H), 8.06-8.13 (m, 1H),7.39-7.45 (m, 1H), 7.26 (m, 1H), 7.09 (m, 1H), 7.02 (d, 1H), 6.91 (d,1H), 6.82 (m, 1H), 5.96 (s., 2H), 4.40 (d, 1H), 4.06 (m, 1H), 3.79 (d,2H), 3.06 (br. s., 1H), 2.31 (m, 1H), 2.11 (m, 1H), 1.90 (m, 2H), 1.64(m, 1H), 1.30 (m, 1H)

Compound I-233

The title compound was prepared following general procedure B, exceptmethyl L-cyclohexylglycine methyl ester (as the HCl salt) was the aminereactant, and the contents were heated to 90° C. as a solution inTHF/water (10:1) for 16 h. Contents cooled, treated with solid sodiumhydroxide, and stirred at 23° C. for 2 h. The organic solvent wasremoved from the reaction mixture, upon completion and the precipitatewas filtered to furnish desired compound, Compound I-233 as a whitesolid (26.0 mg, 0.047 mmol, 70.7% yield).

¹H NMR (500 MHz, METHANOL-d4) δ ppm: 9.08 (d, 1H), 8.12 (d, 1H), 7.42(s, 1H), 7.29-7.35 (m, 1H), 7.25 (d, 1H), 7.18-7.24 (m, 1H), 7.09 (t,1H), 6.93 (t, 1H), 6.77 (d, 1H), 5.82-5.92 (dd, 2H), 4.17 (br. s., 1H),3.30 (s., 1H), 1.79-1.91 (m, 2H), 1.50-1.69 (m, 3H), 0.89-1.24 (m, 5H).

Compound I-243

A mixture of Intermediate 1 (25 mg, (S)-methyl2-amino-2-cyclohexylacetate hydrochloride (41.7 mg, 3 equiv.) andtriethylamine (93 μl, 10 equiv), was heated at 90° C. for 16 hours in amixture of THF/water. The reaction mixture was cooled, NaOH (5.35 mg, 2equiv) was added, and the mixture stirred at room temperature for 2hours. The organic solvent was removed, and the resulting precipitatewas filtered to furnish(R)-2-cyclohexyl-2-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)aceticacid as a white solid (26.0 mg, 0.047 mmol, 70.7% yield).

¹H NMR (500 MHz, METHANOL-d4) δ ppm: 8.75 (d, 1H), 8.11 (d, 1H), 7.41(s, 1H), 7.23-7.29 (m, 1H), 7.00-7.11 (m, 1H), 7.02 (t, 1H), 6.88 (d,1H), 6.83 (t, 1H), 5.95 (s, 2H), 4.73 (d, 1H), 1.97-2.04 (m, 1H), 1.88(t, 2H), 1.80 (d, 2H), 1.70 (d, 1H), 1.17-1.39 (m, 5H). The titlecompound was also prepared following general procedure B, except methylD-cyclohexylglycine methyl ester (as the HCl salt) was the aminereactant (1 equiv.), and the contents were heated to 90° C. for 16 h asa solution in THF/water (10:1). Contents cooled, treated with solidsodium hydroxide, and stirred at 23° C. for 18 h. Contents concentratedin vacuo, and purified via reverse phase HPLC to deliver the desiredcompound, Compound I-243 (1 mg, 3% yield) as a white solid.

Compound I-242

The title compound was prepared in 4 steps:

Step 1: Trans-2-(4-methylphenylsulfonamido)cyclohexanecarboxylic acid

A slurry of trans-2-aminocyclohexanecarboxylic acid (318 mg, 1.0equiv.), p-toluenesulfonyl chloride (508 mg, 1.2 equiv.) and 1M aqueoussodium hydroxide solution (6.7 mL, 3.0 equiv) was heated in water (5 mL)at 90° C. for 1 hour. The reaction mixture was cooled to 0° C., andacidified by the addition of 3M aqueous hydrochloric acid solution. Theresulting white precipitate was filtered and washed successively withwater then ethanol to afford racemictrans-2-(4-methylphenylsulfonamido)cyclohexanecarboxylic acid as a whitesolid (179.6 mg, 27% yield).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.73 (d, 2H), 7.27 (d, 2H), 4.98-5.16(m, 1H), 3.24-3.46 (br. s, 1H), 2.39 (s, 3H), 2.23-2.34 (m, 1H),1.87-2.03 (m, 2H), 1.58-1.78 (m, 2H), 1.42-1.58 (m, 1H), 1.08-1.35 (m,3H).

Step 2: Synthesis oftrans-2-(N,4-dimethylphenylsulfonamido)cyclohexanecarboxylic acid

A solution of trans-2-(4-methylphenylsulfonamido)cyclohexanecarboxylicacid (187 mg, 0.629 mmol), iodomethane (0.124 mL, 3.0 equiv) and 1Maqueous sodium hydroxide solution (2.52 mL, 4.0 equiv) solution in water(5 mL) was heated at 75° C. for 1.5 hours, after which the reactionmixture was cooled to room temperature, washed with dichloromethane(2×30 mL), acidified by the addition of 3M aqueous hydrochloric acidsolution, extracted with dichloromethane (3×30 mL), dried (sodiumsulfate), filtered, and concentrated to afford the crude N-methyl aminoacid product. Purification was achieved using silica gel chromatographywith 2 to 5% methanol in dichloromethane as the eluent over 40 minutes.This affordedtrans-2-(N,4-dimethylphenylsulfonamido)cyclohexanecarboxylic acid as awhite foam (130 mg, 66% yield).

¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.69-7.76 (d, 2H), 7.28 (d, 2H),4.03-4.16 (m, 1H), 2.78 (s, 3H), 2.49-2.61 (m, 1H), 2.43 (s, 3H),2.02-2.13 (m, 1H), 1.73-1.84 (m, 2H), 1.63-1.73 (m, 1H), 1.55-1.63 (m,1H), 1.35-1.45 (m, 2H), 1.10-1.22 (m, 1H).

Step 3: trans-2-(methylamino)cyclohexanecarboxylic acid hydrobromide

To a vial containingtrans-2-(N,4-dimethylphenylsulfonamido)cyclohexanecarboxylic acid (130mg, 1.0 equiv) was added a 33% glacial acetic acid solution of hydrogenbromide (1.2 ml, 53 equiv). The suspension was heated at 85° C. for 2.5hours after which it was diluted in water and washed with diethyl ether(2×30 mL), then concentrated to a gold foamy residue. Recrystallizationof this material from acetone afforded trans-2(methylamino)cyclohexanecarboxylic acid hydrobromide as a cream-coloredsolid (54.4 mg, 55% yield).

¹H NMR (500 MHz, D₂O) δ (ppm): 3.24-3.37 (m, 1H), 2.65 (s, 3H),2.47-2.60 (m, 1H), 2.06-2.20 (m, 2H), 1.76-1.84 (m, 1H), 1.15-1.51 (m,5H).

Step 4: Compound I-242

The title compound was prepared following general procedure B, excepttrans-2 (methylamino) cyclohexanecarboxylic acid (as the HBr salt) wasthe amine reactant, and the contents were heated to 85° C. for 18 h as asolution in THF/water (10:1). Contents cooled, concentrated in vacuo,and purified via reverse phase HPLC to deliver the desired compound,Compound I-242 (1 mg, 3% yield) as a white solid.

¹H NMR (500 MHz, METHANOL-d4) δ ppm: 8.75 (d, 1H), 8.09 (d, 1H), 7.38(s, 1H), 7.23-7.30 (m, 1H), 7.06-7.11 (m, 1H), 7.00-7.05 (m, 1H), 6.89(d, 1H), 6.83 (t, 1H), 5.94 (s, 2H), 3.16-3.24 (m, 3H), 2.79 (br. s.,1H), 2.08 (d, 1H), 1.86-1.97 (m, 2H), 1.81 (d, 2H), 1.45-1.70 (m, 2H),1.34 (dt, 1H)

Compound I-31

The title compound was prepared following general procedure B, except2-amino-1-morpholinoethanone (5 equiv.) was the amine reactant, 3equivalents of triethylamine was used, and the contents were heated to80° C. for 1 h as a solution in THF. Solvent was removed in vacuo, andcontents were taken up in ethyl acetate. The organic layer was washedwith 1N hydrochloric acid solution, water, and brine, dried over sodiumsulfate, filtered, and concentrated in vacuo. The crude material waspurified via silica gel chromatography utilizing a 0 to 100% ethylacetate/hexane gradient to deliver the desired compound, Compound I-31(4.7 mg, 23% yield).

¹H NMR (500 MHz, CDCl₃) δ 8.44-8.52 (m, 1H), 8.14-8.25 (m, 1H),7.19-7.27 (m, 1H), 6.97-7.12 (m, 2H), 6.83-6.91 (m, 1H), 6.61-6.66 (m,1H), 6.00 (s, 2H), 4.39-4.47 (m, 2H), 3.71-3.82 (m, 7H), 3.56-3.63 (m,2H).

Compound I-33

The title compound was prepared following general procedure B, except3-methylmorpholine was the amine reactant, 5 equivalents oftriethylamine was used, and the contents were heated to 60° C. for 18 has a solution in THF, followed by 80° C. for 18 h. Solvent was removedin vacuo, and contents were taken up in ethyl acetate. The organic layerwas washed with 1N hydrochloric acid, water, and brine, dried oversodium sulfate, filtered, and concentrated in vacuo. The crude materialwas purified via silica gel chromatography utilizing a 0-5%methanol/dichloromethane gradient to deliver the desired compound,Compound I-33 (8 mg, 41% yield).

¹H NMR (500 MHz, CDCl₃) δ 8.48 (m, 1H), 8.22 (m, 1H), 7.31 (s, 1H),7.1822 (m, 1H), 6.99 (s, 2H), 6.87 (m, 1H), 6.61 (d, 1H), 5.98 (s, 2H),4.69 (m, 1H), 4.37 (m, 1H), 4.05 (m, 1H), 3.83 (m, 2H), 3.69 (m, 1H),3.4752 (m, 1H), 1.45 (d, 3H).

Compound I-34

The title compound was prepared following general procedure B, exceptmethyl pyrrolidine-2-carboxylate was the amine reactant, 2 equivalentsof triethylamine was used, and the contents were heated to 60° C. for 18h as a solution in THF. Solvent was removed in vacuo, and contents weretaken up in ethyl acetate. The organic layer was washed with 1Nhydrochloric acid solution, water, and brine, dried over sodium sulfate,filtered, and concentrated in vacuo. The crude material was purified viasilica gel chromatography utilizing a 0-5% methanol/dichloromethanegradient to deliver the desired compound, Compound I-34 (10.6 mg, 57%yield).

¹H NMR (500 MHz, CDCl₃) δ 8.47 (m, 1H), 8.20 (m, 1H), 8.17.29 (s, 1H),7.21 (m, 1H), 7.04 (m, 1H), 6.98 (m, 1H), 6.87 (m, 1H), 6.59 (dm, 1H),5.98 (m, 2H), 4.76 (m, 1H), 4.05 (m, 1H), 3.94 (m, 1H), 3.73 (s, 3H),2.35 (m, 1H), 2.17 (m, 3H).

Compound I-35

The title compound was prepared following general procedure B, excepttert-butyl pyrrolidin-3-ylcarbamate was the amine reactant (5 equiv.), 3equivalents of triethylamine was used, and the contents were heated to80° C. for 1 h as a solution in THF. Solvent was removed in vacuo, andcontents were purified via silica gel chromatography utilizing a 0-100%ethyl acetate/hexanes gradient to deliver the desired compound, CompoundI-35 (30 mg, 68% yield).

¹H NMR (500 MHz, CDCl₃) δ 8.44-8.48 (m, 1H), 8.14-8.19 (m, 1H), 7.32 (s,1H), 7.17-7.24 (m, 1H), 6.95-7.08 (m, 2H), 6.82-6.89 (m, 1H), 6.57-6.63(m, 1H), 5.99 (s, 2H), 4.72-4.79 (m, 1H), 4.32-4.43 (m, 1H), 4.00-4.07(m, 1H), 3.86-3.95 (m, 2H), 3.68-3.75 (m, 1H), 2.23-2.33 (m, 1H),1.96-2.05 (m, 1H), 1.48 (s, 9H).

Compound I-41

The title compound was prepared following general procedure B, exceptmethyl pyrrolidine-2-carboxylate was the amine reactant, 2 equivalentsof triethylamine was used, and the contents were heated to 60° C. for 18h as a solution in THF. Solvent was removed in vacuo, and contents weretaken up in ethyl acetate. The organic layer was washed with 1Nhydrochloric acid solution, water, and brine, dried over sodium sulfate,filtered, and concentrated in vacuo. The crude material was purified viasilica gel chromatography utilizing a 0-5% methanol/dichloromethanegradient to deliver the desired compound, Compound I-41 (4 mg, 22%yield).

¹H NMR (500 MHz, CDCl₃) δ 8.44-8.49 (m, 1H), 8.19-8.26 (m, 1H),7.34-7.39 (m, 1H), 7.18-7.25 (m, 1H), 6.92-7.10 (m, 3H), 6.74-6.80 (m,1H), 5.95-6.00 (m, 2H), 4.45-4.51 (m, 2H), 2.42-2.51 (m, 3H), 2.16-2.23(m, 4H).

Compound I-46

The title compound was prepared by treating a solution of Compound I-35in dichloromethane with an equal volume of trifluroacetic acid. Afterstirring at 23° C. for 1 h, solvent was removed under a stream ofnitrogen, and contents were dried under vacuum for 18 h to deliver thedesired compound, Compound I-46 (29 mg) as a solid.

¹H NMR (500 MHz, CD₃OD) δ 8.83-8.87 (m, 1H), 8.37-8.42 (m, 1H),7.59-7.63 (m, 1H), 7.29-7.37 (m, 1H), 7.05-7.16 (m, 2H), 6.94-7.02 (m,2H), 6.04 (s, 2H), 4.13-4.33 (m, 5H), 2.53-2.64 (m, 1H), 2.27-2.39 (m,1H).

Compound I-48

The title compound was prepared following general procedure B, exceptmethyl piperidine-2-carboxylate was the amine reactant, 2 equivalents oftriethylamine was used, and the contents were heated to 60° C. for 18 has a solution in THF. Solvent was removed in vacuo, and contents weretaken up in ethyl acetate. The organic layer was washed with 1Nhydrochloric acid solution, water, and brine, dried over sodium sulfate,filtered, and concentrated in vacuo. The crude material was purified viareverse phase HPLC to deliver the desired compound, Compound I-48 (3.7mg, 18% yield).

¹H NMR (400 MHz, CDCl₃) δ 8.46-8.50 (m, 1H), 8.37-8.44 (m, 1H),7.32-7.37 (m, 1H), 7.17-7.23 (m, 1H), 6.97-7.09 (m, 3H), 6.59-6.62 (m,1H), 5.91 (s, 2H), 5.46-5.57 (m, 1H), 4.54-4.67 (m, 1H), 3.75 (s, 3H),3.38-3.47 (m, 1H), 2.34-2.45 (m, 1H), 1.78-1.89 (m, 3H), 1.61-1.72 (m,1H), 1.45-1.55 (m, 1H).

Compound I-53

The title compound was prepared following general procedure B, exceptazetidine-3-carboxylic acid was the amine reactant (5 equiv.), 3equivalents of triethylamine was used, and the contents were heated to75° C. for 18 h as a solution in THF. Solvent was removed under a streamof nitrogen. Product isolated via reverse phase HPLC to deliver thedesired compound, Compound I-53 (15.4 mg, 88% yield).

¹H NMR (500 MHz, METHANOL-d₄) δ 8.81-8.85 (m, 1H), 8.22-8.27 (m, 1H),7.55-7.59 (m, 1H), 7.29-7.36 (m, 1H), 7.05-7.16 (m, 2H), 6.93-6.99 (m,2H), 5.99-6.05 (m, 2H), 4.65-4.84 (m, 4H), 3.75-3.84 (m, 1H).

Compound I-54

The title compound was prepared following general procedure B, except3-methylpiperazin-2-one was the amine reactant (5 equiv.), 3 equivalentsof triethylamine was used, and the contents were heated to 75° C. for 18h as a solution in THF. Solvent was removed under a stream of nitrogen.Product isolated via reverse phase HPLC to deliver the desired compound,Compound I-54 (1.4 mg, 8% yield).

¹H NMR (500 MHz, CDCl₃) δ 8.53-8.55 (m, 1H), 8.49-8.53 (m, 1H),7.43-7.48 (m, 1H), 7.31-7.37 (m, 1H), 7.24-7.28 (m, 1H), 7.09-7.14 (m,1H), 7.02-7.08 (m, 2H), 6.67-6.70 (m, 1H), 5.97 (s, 2H), 5.34-5.47 (m,1H), 4.89-4.95 (m, 1H), 3.62-3.78 (m, 2H), 3.50-3.60 (m, 1H), 1.70 (d,3H).

Compound I-55

The title compound was prepared following general procedure B, exceptazetidine-2-carboxylic acid (5 equiv.) was the amine reactant, 5equivalents of triethylamine was used, and the contents were heated to75° C. for 18 h as a solution in THF. Solvent was removed in vacuo, andcontents were purified via reverse phase HPLC to deliver the desiredcompound, Compound I-55 (1.3 mg, 2% yield).

¹H NMR (500 MHz, CD₃OD) δ 8.82 (s, 1H), 8.23-8.29 (m, 1H), 7.40-7.52 (m,1H), 7.28-7.35 (m, 1H), 7.04-7.16 (m, 2H), 6.93 (br. s., 2H), 5.98-6.03(m, 2H), 5.23-5.36 (m, 1H), 4.42-4.67 (m, 2H), 2.92-3.07 (m, 1H),2.50-2.62 (m, 1H).

Compound I-56

The title compound was prepared following general procedure B, except3-fluoropiperidine (5 equiv.) was the amine reactant, 5 equivalents oftriethylamine was used, and the contents were heated to 75° C. for 18 has a solution in THF. Solvent was removed in vacuo, and contents werepurified via reverse phase HPLC to deliver the desired compound,Compound I-56 (1.3 mg, 2% yield).

¹H NMR (500 MHz, CHLOROFORM-d) δ 8.52-8.56 (m, 1H), 8.45-8.50 (m, 1H),7.49-7.54 (m, 1H), 7.24-7.28 (m, 1H), 7.13-7.20 (m, 1H), 7.01-7.11 (m,2H), 6.68 (s, 1H), 5.95 (s, 2H), 4.85-5.03 (m, 1H), 4.56-4.81 (m, 2H),3.71-3.89 (m, 1H), 3.47-3.60 (m, 1H), 1.75-2.26 (m, 4H).

Compound I-57

The title compound was prepared following general procedure B, except3,3-difluoropiperidine (5 equiv.) was the amine reactant, 5 equivalentsof triethylamine was used, and the contents were heated to 75° C. for 18h as a solution in THF. Solvent was removed in vacuo, and contents werepurified via reverse phase HPLC to deliver the desired compound,Compound I-57 (4.5 mg, 5% yield).

¹H NMR (500 MHz, CDCl₃) δ 8.52-8.55 (m, 1H), 8.47-8.52 (m, 1H),7.40-7.45 (m, 1H), 7.24-7.28 (m, 1H), 7.11-7.17 (m, 1H), 7.02-7.10 (m,2H), 6.65-6.68 (m, 1H), 5.93-5.98 (m, 2H), 4.20-4.30 (m, 2H), 4.00-4.08(m, 2H), 2.16-2.27 (m, 2H), 1.96-2.05 (m, 2H).

Compound I-58

A solution of Compound I-48 was dissolved in THF, and an aqueoussolution of lithium hydroxide (3 equiv.) was added. The solution wasstirred at 25° C. for 18 h. Contents were concentrated and the remainingaqueous layer was acidified with 1N hydrochloric acid solution whichresulted in a white precipitate. The aqueous layer was extracted withethyl acetate, and the combined organic layers were washed with waterand brine. Contents dried over sodium sulfate, filtered, andconcentrated to deliver the desired compound, Compound I-58 (29 mg, 100%yield).

¹H NMR (400 MHz, CD₃OD) δ 8.75 (m, 1H), 8.20 (m, 1H), 7.42 (m, 1H), 7.26(m, 1H), 6.98-7.11 (m, 2H), 6.84 (m, 2H), 5.95 (s, 2H), 5.47 (m, 1H),4.52 (m, 1H), 3.44 (m, 1H), 2.31-2.40 (m, 1H), 1.93 (m, 1H), 1.81 (m,2H), 1.68 (m, 1H), 1.54 (m, 1H).

Compound I-59

The title compound was prepared following general procedure B, exceptpiperazin-2-one was the amine reactant (5 equiv.), 5 equivalents oftriethylamine was used, and the contents were heated to 75° C. for 18 has a solution in THF. Solvent was removed under a stream of nitrogen andcontents were purified via reverse phase HPLC to deliver the desiredcompound, Compound I-59 (1.6 mg, 2% yield).

¹H NMR (500 MHz, CDCl_(3′)) δ 8.51-8.54 (m, 1H), 8.45-8.49 (m, 1H),7.69-7.73 (m, 1H), 7.23-7.27 (m, 1H), 7.03-7.09 (m, 3H), 6.69-6.73 (m,2H), 6.00-6.03 (m, 2H), 4.70-4.73 (m, 2H), 4.26-4.32 (m, 2H), 3.64-3.69(m, 2H).

Compound I-60

The title compound was prepared following general procedure B, excepttriethylamine was the amine reactant (2 equiv.), and the contents wereheated to 60° C. for 18 h as a solution in THF. Solvent was removed invacuo, and contents were taken up in ethyl acetate. The organic layerwas washed with 1N hydrochloric acid solution, water, and brine, driedover sodium sulfate, filtered, and concentrated in vacuo. The crudematerial was purified via reverse phase HPLC to deliver the desiredcompound, Compound I-60 (1.9 mg, 11% yield).

¹H NMR (400 MHz, CD₃OD) δ 8.77-8.81 (m, 1H), 8.17-8.22 (m, 1H),7.48-7.52 (m, 1H), 7.23-7.32 (m, 1H), 7.01-7.13 (m, 2H), 6.89-6.98 (m,2H), 5.96-6.01 (m, 2H), 3.81-3.90 (m, 4H), 1.34 (s, 6H).

Compound I-66

The title compound was prepared following general procedure B, exceptpiperidine-3-carboxamide was the amine reactant (5 equiv.), 8equivalents of triethylamine was used, and the contents were heated to75° C. for 18 h as a solution in THF. Solvent was removed and crudematerial was purified via reverse phase HPLC to deliver the desiredcompound, Compound I-66 (7 mg, 36% yield).

¹H NMR (500 MHz, CDCl₃) δ 8.51-8.55 (m, 1H), 8.25-8.31 (m, 1H),7.47-7.52 (m, 1H), 7.22-7.27 (m, 1H), 7.09-7.16 (m, 1H), 7.00-7.09 (m,2H), 6.83-6.90 (m, 1H), 6.67-6.72 (m, 1H), 6.17-6.22 (m, 1H), 5.90-5.95(m, 2H), 4.52-4.60 (m, 1H), 4.30-4.43 (m, 1H), 3.81-3.90 (m, 1H),3.60-3.69 (m, 1H), 2.69-2.81 (m, 1H), 2.05-2.13 (m, 2H), 1.92-2.00 (m,1H), 1.69-1.81 (m, 1H).

Compound I-75

The title compound was prepared following general procedure B, exceptmethyl azepane-2-carboxylate was the amine reactant (1.5 equiv.),potassium carbonate (4 equiv.) was used instead of triethylamine, andthe contents were heated to 150° C. for 10 min in the microwave as asolution in NMP. The resulting mixture was filtered to remove the solidpotassium carbonate, and concentrated in vacuo. The crude material waspurified via reverse phase HPLC using a 20-70% acetonitrile/water (with0.1% TFA) gradient to deliver the desired compound, Compound I-75 (1 mg,3% yield).

¹H NMR (500 MHz, CDCl₃) δ 8.83 (m, 1H), 8.33 (m, 1H), 7.48 (m, 1H), 7.31(m, 1H), 7.10 (m, 2H), 6.91 (m, 2H), 6.01 (s, 2H), 5.04 (m, 1H), 4.18(m, 1H), 3.73 (m, 1H), 2.58 (m, 1H), 2.04 (m, 3H), 1.92 (m, 1H), 1.79(m, 1H), 1.53 (m, 2H).

Compound I-82

The title compound was prepared following general procedure B, except(1R,3S,5S)-8-azabicyclo[3.2.1]octan-3-ylmethanol (as the HCl salt) wasthe amine reactant (3.5 equiv.), 5 equivalents of triethylamine wasused, and the contents were heated to 120° C. for 30 min in themicrowave as a solution in NMP. The resulting mixture was purified viareverse phase HPLC to deliver the desired compound, Compound I-82 (10.8mg, 42% yield).

¹H NMR (500 MHz, METHANOL-d₄) δ 8.82-8.86 (m, 1H), 8.25-8.29 (m, 1H),7.62-7.66 (m, 1H), 7.30-7.36 (m, 1H), 7.05-7.15 (m, 2H), 6.92-7.02 (m,2H), 6.00-6.06 (m, 2H), 3.66-3.72 (m, 2H), 2.10-2.40 (m, 4H), 1.78-2.07(m, 5H).

Compound I-83

The title compound was prepared following general procedure B, exceptmorpholine-2-carboxylic acid (as the HCl salt) was the amine reactant (2equiv.), Hunig's base (3 equiv.) was used in place of triethylamine, andcontents were heated to 120° C. for 30 min in the microwave as asolution in NMP. The resulting mixture was purified via reverse phaseHPLC using a 0-95% acetonitrile/water (with 0.1% TFA) gradient todeliver the desired compound, Compound I-83 (10.8 mg, 42% yield) as aclear glass.

¹H NMR (500 MHz, METHANOL-d₄) δ 8.81-8.85 (m, 1H), 8.35-8.44 (m, 1H),7.64 (s, 1H), 7.26-7.35 (m, 1H), 7.04-7.14 (m, 2H), 6.97 (d, 2H), 6.02(s, 2H), 4.73 (m, 1H), 4.46 (m, 2H), 4.14-4.20 (m, 1H), 3.97 (m, 1H),3.89 (d, 2H).

Compound I-87

The title compound was prepared following general procedure B, except(R)-piperidine-2-carboxylic acid (4 equiv.) was the amine reactant, 5equivalents of triethylamine was used, and the contents were heated to90° C. for 18 h as a solution in THF/water (9:1). Solvent was removedunder a stream of nitrogen, and the crude material was purified viareverse phase HPLC using a 20-51% acetonitrile/water (in 0.1% TFA)gradient to deliver the desired compound, Compound I-87 (12 mg, 48%yield).

¹H NMR (500 MHz, METHANOL-d₄) δ 8.79-8.83 (m, 1H), 8.34-8.39 (m, 1H),7.60 (s, 1H), 7.27-7.35 (m, 1H), 7.03-7.15 (m, 2H), 6.90-6.98 (m, 2H),6.02 (s, 2H), 4.61-4.83 (m, 1H), 3.43-3.58 (m, 1H), 2.43-2.51 (m, 1H),1.69-2.02 (m, 5H), 1.55-1.69 (m, 1H).

Compound I-84

The title compound was prepared following general procedure B, except(S)-piperidine-2-carboxylic acid (4 equiv.) was the amine reactant, 5equivalents of triethylamine was used, and the contents were heated to90° C. for 18 h as a solution in THF/water (9:1). Solvent was removedunder a stream of nitrogen, and the crude material was purified viareverse phase HPLC using a 20-51% acetonitrile/water (in 0.1% TFA)gradient to deliver the desired compound, Compound I-84 (9.6 mg, 39%yield).

¹H NMR (500 MHz, METHANOL-d₄) δ 8.79-8.83 (m, 1H), 8.31-8.36 (m, 1H),7.54-7.58 (m, 1H), 7.27-7.34 (m, 1H), 7.04-7.15 (m, 2H), 6.89-6.97 (m,2H), 6.01 (s, 2H), 5.65 (br. s., 1H), 4.58-4.80 (m, 1H), 3.42-3.57 (m,1H), 2.41-2.50 (m, 1H), 1.67-2.02 (m, 4H), 1.55-1.66 (m, 1H).

Compound I-95

The title compound was prepared following general procedure B, except(R)-morpholine-3-carboxylic acid (4 equiv.) was the amine reactant,Hunig's base (5 equiv.) was used instead of triethylamine, and thecontents were heated to 90° C. for 18 h as a solution in THF/water(9:1). Solvent was removed under a stream of nitrogen, and the crudematerial was purified via reverse phase HPLC using a 20-51%acetonitrile/water (in 0.1% TFA) gradient to deliver the desiredcompound, Compound I-95 (19 mg, 76% yield).

¹H NMR (500 MHz, CD₃OD) δ 8.81 (d, 1H), 8.39 (d, 1H), 7.57 (s, 1H),7.26-7.34 (m, 1H), 7.02-7.16 (m, 2H), 6.93 (d, 2H), 6.00 (s, 2H),5.26-5.59 (m, 1H), 4.55 (d, 2H), 4.04 (s, 1H), 3.93 (dd, 1H), 3.62-3.80(m, 2H).

Compound I-96

The title compound was prepared following general procedure B, except(S)-morpholine-3-carboxylic acid (4 equiv.) was the amine reactant,Hunig's base (5 equiv.) was used instead of triethylamine, and thecontents were heated to 90° C. for 18 h as a solution in THF/water(9:1). Solvent was removed under a stream of nitrogen, and the crudematerial was purified via reverse phase HPLC using a 20-51%acetonitrile/water (in 0.1% TFA) gradient to deliver the desiredcompound, Compound I-96 (8 mg, 31% yield).

¹H NMR (500 MHz, METHANOL-d₄) δ 8.81 (s, 1H), 8.34-8.42 (m, 1H),7.51-7.59 (m, 1H), 7.27-7.35 (m, 1H), 7.02-7.15 (m, 2H), 6.94 (s, 2H),6.01 (s, 2H), 5.37-5.54 (m, 1H), 4.56 (d, 2H), 4.01-4.09 (m, 1H),3.89-3.96 (m, 1H), 3.61-3.81 (s, 2H).

Compound I-97

The title compound was prepared following general procedure B, except1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (4 equiv.) was theamine reactant, Hunig's base (5 equiv.) was used instead oftriethylamine, and the contents were heated to 90° C. for 18 h as asolution in THF/water (9:1). Solvent was removed under a stream ofnitrogen, and contents were taken up in ethyl acetate. The organic layerwas washed with 1N hydrochloric acid solution, water, and brine, driedover sodium sulfate, filtered, and concentrated in vacuo. The crudematerial was purified via reverse phase HPLC to deliver the desiredcompound, Compound I-97 (3.4 mg, 12% yield) as a solid.

¹H NMR (500 MHz, METHANOL-d₄) δ 8.84-8.89 (m, 1H), 8.42-8.49 (m, 1H),7.62-7.69 (m, 2H), 7.30-7.40 (m, 4H), 7.06-7.16 (m, 2H), 6.97 (m, 2H),6.12-6.18 (m, 1H), 6.05 (s, 2H), 4.48-4.58 (m, 1H), 4.14-4.23 (m, 2H),3.05-3.15 (m, 1H).

Compound I-98

The title compound was prepared following general procedure B, except3-methyl-5-(piperidin-2-yl)-1,2,4-oxadiazole (4 equiv.) was the aminereactant, Hunig's base (5 equiv.) was used instead of triethylamine, andthe contents were heated to 90° C. for 18 h as a solution in THF/water(9:1). Solvent was removed under a stream of nitrogen, and contents weretaken up in ethyl acetate. The organic layer was washed with 1Nhydrochloric acid solution, water, and brine, dried over sodium sulfate,filtered, and concentrated in vacuo. The crude material was purified viareverse phase HPLC to deliver the desired compound, Compound I-98 (5.3mg, 20% yield) as a solid.

¹H NMR (500 MHz, METHANOL-d₄) δ 8.77-8.83 (m, 1H), 8.37-8.45 (m, 1H),7.54 (s, 1H), 7.26-7.36 (m, 1H), 7.03-7.17 (m, 2H), 6.93 (s, 2H),6.48-6.55 (m, 1H), 6.00 (s, 2H), 4.60-4.75 (m, 1H), 3.45-3.55 (m, 1H),2.49-2.58 (m, 1H), 2.38 (s, 3H), 2.15-2.27 (m, 1H), 1.74-1.94 (m, 3H),1.59-1.73 (m, 1H).

Compound I-99

The title compound was prepared following general procedure B, exceptmethyl morpholine-3-carboxylate (4 equiv.) was the amine reactant,Hunig's base (3 equiv.) was used instead of triethylamine, and thecontents were heated to 120° C. for 2 h as a solution in NMP. Solventwas removed and the crude material was purified via reverse phase HPLCto deliver the desired compound, Compound I-99 (7 mg, 25% yield) as asolid.

¹H NMR (400 MHz, CD₃OD) δ 8.71-8.75 (m, 1H), 8.21-8.26 (m, 1H),7.39-7.43 (m, 1H), 7.19-7.29 (m, 1H), 6.97-7.12 (m, 2H), 6.85-6.88 (m,1H), 6.75-6.82 (m, 1H), 5.90-5.95 (m, 2H), 5.20-5.31 (m, 1H), 4.45 (s,1H), 3.93-4.01 (m, 1H), 3.82-3.93 (m, 2H), 3.66-3.75 (m, 2H).

Compound I-105

The title compound was prepared following general procedure B, exceptpiperidine-2-carboxamide (4 equiv.) was the amine reactant, 6equivalents of triethylamine was used, and the contents were heated to60° C. for 48 h as a solution in THF/water (9:1). Solvent was removedunder a stream of nitrogen, and the crude material was purified viareverse phase HPLC using a 20-51% acetonitrile/water (in 0.1% TFA)gradient to deliver the desired compound, Compound I-105 (12 mg, 48%yield) as a solid.

¹H NMR (500 MHz, METHANOL-d₄) δ 8.80-8.87 (m, 1H), 8.35-8.41 (m, 1H),7.58-7.65 (m, 1H), 7.28-7.36 (m, 1H), 7.05-7.16 (m, 2H), 6.91-7.02 (m,2H), 6.03 (s, 2H), 5.53-5.61 (m, 1H), 4.65-4.77 (m, 1H), 3.56-3.69 (m,1H), 2.37-2.46 (m, 1H), 1.62-2.07 (m, 6H).

Compound I-106

The title compound was prepared following general procedure B, except4-aminotetrahydro-2H-pyran-4-carboxylic acid (3.5 equiv.) was the aminereactant, 5 equivalents of triethylamine was used, and the contents wereheated to 200° C. for 10 min in the microwave as a solution in NMP. Thereaction mixture was diluted with water and filtered. The filtrate wasbasified to pH 10 with 3N sodium hydroxide solution, and extracted withdichloromethane. The filtrate was then acidified to pH 1 with 1Nhydrochloric acid solution and extracted with dichloromethane. Theorganic layer was concentrated in vacuo, and the crude material waspurified via reverse phase HPLC to deliver the desired compound,Compound I-106 (2.3 mg, 9% yield) as a solid.

¹H NMR (500 MHz, METHANOL-d₄) δ 8.81-8.87 (m, 1H), 8.31-8.35 (m, 1H),7.38-7.41 (m, 1H), 7.25-7.34 (m, 1H), 7.04-7.15 (m, 2H), 6.89-6.98 (m,2H), 6.01 (s, 2H), 3.87-3.96 (m, 2H), 3.76-3.87 (m, 2H), 2.36-2.45 (m,2H), 2.23-2.33 (m, 2H).

Compound I-110

The title compound was prepared following general procedure B, except4-amino-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (3 equiv.)was the amine reactant, 5 equivalents of triethylamine was used, and thecontents were heated to 120° C. for 18 h as a solution in DMSO. Withoutworkup, the crude material was purified via reverse phase HPLC todeliver the desired compound, Compound I-110 (8.2 mg, 26% yield) as asolid.

¹H NMR (500 MHz, METHANOL-d₄) δ 8.83 (s, 1H), 8.31-8.36 (m, 1H), 7.39(s, 1H), 7.26-7.36 (m, 1H), 7.02-7.14 (m, 2H), 6.91 (s, 2H), 6.00 (s,2H), 3.75-3.88 (m, 2H), 3.36-3.49 (m, 2H), 2.29 (br. s., 4H), 1.50 (s,9H).

Compound I-111

The title compound was prepared following general procedure B, except1,2,3,4-tetrahydroisoquinoline (2.5 equiv.) was the amine reactant, notriethylamine was used, and the contents were heated to 120° C. for 18 has a solution in THF. Solvent was removed under a stream of nitrogen,and the crude material was purified via reverse phase HPLC using a20-51% acetonitrile/water (in 0.1% TFA) gradient to deliver the desiredcompound, Compound I-111 (13.9 mg, 55% yield) as a solid.

¹H NMR (500 MHz, METHANOL-d₄) δ 8.82-8.86 (m, 1H), 8.28-8.34 (m, 1H),7.68-7.73 (m, 1H), 7.24-7.35 (m, 6H), 6.93-7.15 (m, 5H), 6.00-6.06 (m,2H), 5.24 (s, 2H), 4.27-4.33 (m, 2H), 3.10-3.16 (m, 2H).

Compound I-122

In a 25 ml flask was dissolved Compound I-110 (0056 g, 0.096 mmol) inDCM (Volume: 2 ml), and TFA (2 mL, 26.0 mmol). After stirring for 3 h atroom temperature, the reaction was complete. The solvent was removed invacuo to give pure product, Compound I-122 (13.9 mg, 55% yield) as awhite solid.

¹H NMR (500 MHz, METHANOL-d₄) δ 8.78-8.86 (m, 1H), 8.30-8.38 (m, 1H),7.26-7.38 (m, 2H), 7.01-7.15 (m, 2H), 6.84-6.96 (m, 2H), 5.97 (s, 2H),3.36-3.51 (m, 4H), 2.50-2.67 (m, 4H).

Compound I-126

The title compound was prepared following general procedure B, except6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (3 equiv.)was the amine reactant, no triethylamine was used, and the contents wereheated to 120° C. for 18 h as a solution in DMSO. The reaction mixturewas filtered, and directly purified via reverse phase HPLC to deliverthe desired compound, Compound I-126 (11 mg, 38% yield) as a solid.

¹H NMR (500 MHz, METHANOL-d₄) δ 8.82-8.85 (m, 1H), 8.33-8.37 (m, 1H),7.53-7.59 (m, 2H), 7.27-7.34 (m, 1H), 7.10 (m, 2H), 6.86-6.97 (m, 4H),5.01 (s, 2H), 5.96 (m, 1H), 4.35-4.45 (m, 1H), 4.04-4.15 (m, 1H), 3.84(s, 3H), 3.04 (m, 2H).

Compound I-127

The title compound was prepared following general procedure B, except6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (3 equiv.)was the amine reactant, no triethylamine was used, and the contents wereheated to 120° C. for 18 h as a solution in DMSO. The reaction mixturewas filtered, and directly purified via reverse phase HPLC to deliverthe desired compound, Compound I-127 (5.2 mg, 18% yield) as a solid.

¹H NMR (500 MHz, METHANOL-d₄) δ 8.83-8.87 (m, 1H), 8.37-8.42 (m, 1H),7.57-7.63 (m, 1H), 7.42-7.48 (m, 1H), 7.28-7.36 (m, 1H), 7.05-7.16 (m,2H), 6.90-7.00 (m, 2H), 6.71-6.80 (m, 2H), 6.02 (s, 2H), 5.94-5.99 (m,1H), 4.42-4.51 (m, 1H), 3.99-4.13 (m, 1H), 3.16-3.27 (m, 2H), 2.94-3.02(m, 1H).

Compound I-128

The title compound was prepared following general procedure B, except5-fluoro-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (3 equiv.) wasthe amine reactant, no triethylamine was used, and the contents wereheated to 60° C. for 18 h as a solution in DMSO, followed by heating to120° C. for 1 h. The reaction mixture was filtered, and directlypurified via reverse phase HPLC to deliver the desired compound,Compound I-128 (5.7 mg, 20% yield) as a solid.

¹H NMR (500 MHz, CD₃OD) δ 8.83 (m, 1H), 8.31 (m, 1H), 7.68 (m, 1H), 7.28(m, 2H), 7.03 (m, 6H), 6.02 (s, 2H), 5.21 (s, 2H), 4.27 (m, 2H), 3.08(m, 2H).

Compound I-130

A solution of Compound I-122 (as the TFA salt) in dichloromethane wastreated with triethylamine (2 equiv.) and propionyl chloride (1.1equiv.) at 25° C. Reaction was stirred at 25° C. for 18 h. A slurryremained, so contents treated with 5 drops of NMP (contents go clear),and 1 additional equivalents of both propionyl chloride andtriethylamine. Contents were then stirred at 25° C. for 18 h. Solventwas removed in vacuo and the crude material was purified via reversephase HPLC to deliver the desired compound, Compound I-130 (5.5 mg, 47%yield) as a solid.

¹H NMR (500 MHz, METHANOL-d₄) δ 8.82-8.86 (m, 1H), 8.33-8.38 (m, 1H),7.38-7.42 (m, 1H), 7.28-7.36 (m, 1H), 7.05-7.15 (m, 2H), 6.89-6.99 (m,2H), 6.00 (s, 2H), 4.04-4.13 (m, 1H), 3.82-3.92 (m, 1H), 3.55-3.64 (m,1H), 3.44-3.52 (m, 1H), 2.21-2.52 (m, 7H), 1.16 (t, 3H).

Compound I-131

A solution of Compound I-122 (as the TFA salt) in dichloromethane wastreated with triethylamine (2 equiv.) and methyl carbonochloridate (1.1equiv.) at 25° C. Reaction was stirred at 25° C. for 18 h. A slurryremained, so contents treated with 5 drops of NMP (contents go clear),and 1 additional equivalents of both methyl carbonochloridate andtriethylamine. Contents were then stirred at 25° C. for 18 h. Solventwas removed in vacuo and the crude material was purified via reversephase HPLC to deliver the desired compound, Compound I-131 (3.8 mg, 32%yield) as a solid.

¹H NMR (500 MHz, METHANOL-d₄) δ 8.81-8.86 (m, 1H), 8.30-8.37 (m, 1H),7.39 (s, 1H), 7.26-7.34 (m, 1H), 7.04-7.15 (m, 2H), 6.93 (m, 2H), 6.00(s, 2H), 3.88 (m, 2H), 3.73 (s, 3H), 3.42-3.52 (m, 2H), 2.28-2.34(br.s., 4H).

Compound I-132

A solution of Compound I-122 (as the TFA salt) in dichloromethane wastreated with triethylamine (2 equiv.) and ethyl isocyanate (1.1 equiv.)at 25° C. Reaction was stirred at 25° C. for 18 h. A slurry remained, socontents treated with 5 drops of NMP (contents go clear), and 1additional equivalents of both ethyl isocyanate and triethylamine.Contents were then stirred at 25° C. for 18 h. Solvent was removed invacuo and the crude material was purified via reverse phase HPLC todeliver the desired compound, Compound I-132 (5.9 mg, 49% yield) as asolid.

¹H NMR (500 MHz, METHANOL-d₄) δ 8.83-8.86 (m, 1H), 8.32-8.37 (m, 1H),7.38-7.41 (m, 1H), 7.28-7.34 (m, 1H), 7.05-7.15 (m, 2H), 6.89-6.99 (m,2H), 6.00 (s, 2H), 3.74-3.83 (m, 2H), 3.37-3.45 (m, 2H), 3.19-3.26 (m,2H), 2.30 (s, 4H), 1.14 (s, 3H).

Compound I-153

The title compound was prepared following general procedure B, except2-(methylamino)benzoic acid was the amine reactant, 5 equivalents oftriethylamine was used, and the contents were heated to 120° C. for 12 has a solution in THF. Solvent was removed under vacuum and the crudematerial was purified via reverse phase HPLC to deliver the desiredcompound, Compound I-153 (5.5 mg, 40% yield) as a solid.

¹H NMR (500 MHz, METHANOL-d₄) δ 8.80-8.85 (m, 1H), 8.12-8.21 (m, 2H),7.71-7.78 (m, 1H), 7.53-7.64 (m, 3H), 7.28-7.36 (m, 1H), 7.06-7.17 (m,2H), 6.91-7.02 (m, 2H), 6.04 (s, 2H), 3.72 (s, 3H).

Compound I-161 and Compound I-162

The title compounds were prepared following general procedure B, except3-methylpiperidine-2-carboxylic acid was the amine reactant, Hunig'sbase (5 equiv.) was used instead of triethylamine, and the contents wereheated to 120° C. for 18 h as a solution in THF/water (5:1). Solvent wasremoved under vacuum and the crude material was purified via reversephase HPLC to deliver the desired compounds, Compound 1-161 (cis,racemic, 5.1 mg, 20% yield) as a solid and Compound I-162 (trans,racemic, 1.3 mg, 5%) as a solid.

¹H NMR (400 MHz, CD₃OD) Compound 1-161 δ 8.77-8.80 (m, 1H), 8.30-8.34(m, 1H), 7.52-7.56 (m, 1H), 7.23-7.32 (m, 1H), 6.99-7.12 (m, 2H),6.87-6.94 (m, 2H), 5.98 (s, 2H), 5.24-5.30 (m, 1H), 4.50-4.61 (m, 1H),3.72-3.83 (m, 1H), 2.09-2.21 (m, 1H), 1.91-2.00 (m, 1H), 1.72-1.81 (m,2H), 1.48-1.62 (m, 1H), 1.22 (d, J=7.43 Hz, 3H).

¹H NMR (400 MHz, CD₃OD) Compound I-162 S 8.78-8.80 (m, 1H), 8.31-8.35(m, 1H), 7.55-7.58 (m, 1H), 7.24-7.32 (m, 1H), 7.01-7.12 (m, 2H),6.87-6.96 (m, 2H), 5.99 (s, 2H), 5.29-5.39 (m, 1H), 3.44-3.57 (m, 1H),2.67-2.75 (m, 1H), 1.78-2.03 (m, 3H), 1.54-1.72 (m, 2H), 1.19 (d, 3H).

Compound I-197

The title compound was prepared following general procedure B, except2-(piperidin-4-yloxy)acetic acid was the amine reactant, Hunig's base (5equiv.) was used instead of triethylamine, and the contents were heatedto 100° C. for 18 h as a solution in THF/water (10:1). Solvent wasremoved in vacuo and the crude material was purified via reverse phaseHPLC to deliver the desired compound, Compound I-197 (3 mg, 11% yield)as a solid.

¹H NMR (500 MHz, METHANOL-d₄) δ 8.80-8.84 (m, 1H), 8.24-8.30 (m, 1H),7.57-7.64 (m, 1H), 7.29-7.35 (m, 1H), 7.05-7.16 (m, 2H), 6.92-7.01 (m,2H), 6.00-6.05 (m, 2H), 4.28-4.36 (m, 2H), 4.23 (s, 2H), 3.97-4.05 (m,2H), 3.82-3.89 (m, 1H), 2.05-2.16 (m, 2H), 1.87-1.95 (m, 2H).

Compound I-214

The title compound was prepared following general procedure B, except4-aminobutanoic acid was the amine reactant, and the contents werestirred for 14 h. The crude material was purified via silica gelchromatography utilizing a 0-10% methanol/dichloromethane gradient todeliver the desired compound, Compound I-214 (20 mg, 57% yield) as awhite solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 12.09 (bs, 1H), 9.08 (d, 1H), 8.21 (d, 1H),8.19 (bs, 1H), 7.55 (s, 1H), 7.33-7.27 (m, 1H), 7.21-7.18 (m, 2H), 7.08(ddd, 1H), 6.82 (t, 1H), 5.88 (s, 2H), 3.50 (dd, 2H), 2.30 (dd, 2H),1.86-1.79 (m, 2H).

Compound I-215

The title compound was prepared following general procedure B, except4-(methylamino)butanoic acid was the amine reactant. The crude materialwas purified via silica gel chromatography utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-215 (31 mg, 81% yield) as a solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.10 (d, 1H), 8.35 (d, 1H), 7.67 (s, 1H),7.33-7.28 (m, 1H), 7.22-7.18 (m, 2H), 7.08 (t, 1H), 6.86 (t, 1H), 5.90(s, 2H), 1.88 (t, 2H), 3.30 (d, 3H), 2.30 (t, 2H), 1.90-1.82 (m, 2H).

Compound I-219

The title compound was prepared following general procedure B, exceptN-methyl-D-valine was the amine reactant. The crude material waspurified via silica gel chromatography utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-219 (17 mg, 43% yield) as a solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.74 (d, 1H), 8.17 (d, 1H), 7.41 (s, 1H),7.27-7.22 (m, 1H), 7.09-6.98 (m, 2H), 6.87 (d, 1H), 6.81 (t, 1H), 5.93(s, 2H), 4.71 (d, 1H), 3.31 (s, 3H), 2.51-2.43 (m, 1H), 1.14 (d, 3H),0.96 (d, 3H).

Compound I-221

The title compound was prepared following general procedure B, exceptN-methyl-D-leucine was the amine reactant. The crude material waspurified via silica gel chromatography utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-221 (31 mg, 76% yield) as a solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 12.86 (bs, 1H), 9.07 (d, 1H), 8.29 (d, 1H),7.44 (s, 1H), 7.32-7.27 (m, 1H), 7.20-7.15 (m, 1H), 7.16 (d, 1H),7.08-7.05 (m, 1H), 6.85 (t, 1H), 5.83 (dd, 2H), 3.12 (d, 3H), 3.05-3.00(m, 1H), 1.91-1.82 (m, 1H), 1.76-1.68 (m, 1H), 1.51-1.47 (m, 1H), 0.89(d, 3H), 0.85 (d, 3H).

Compound I-185

The title compound was prepared following general procedure B, except3-(trifluoromethyl)pyrrolidine-3-carboxylic acid was the amine reactant.The crude material was purified via silica gel chromatography utilizinga 0-10% methanol/dichloromethane gradient to deliver the desiredcompound, Compound I-185 (51 mg, 87% yield) as a solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.05 (d, 1H), 8.29 (d, 1H), 7.53 (s, 1H),7.29 (q, 1H), 7.24 (d, 1H), 7.21-7.16 (m, 1H), 7.07 (t, 1H), 6.78 (t,1H), 5.88 (s, 2H), 4.29 (d, 1H), 3.98 (d, 1H), 3.95-3.75 (m, 2H),2.64-2.37 (m, 2H).

Compound I-180

The title compound was prepared following general procedure B, except2-amino-4,4,4-trifluorobutanoic acid was the amine reactant. The crudematerial was purified via silica gel chromatography utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-180 (24 mg, 58% yield) as a solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 13.29 (bs, 1H), 9.07 (d, 1H), 8.26 (d, 1H),8.15-8.12 (m, 1H), 7.39 (s, 1H), 7.28 (q, 1H), 7.18 (t, 1H), 7.15 (s,1H), 7.07 (t, 1H), 6.83 (t, 1H), 5.84 (s, 2H), 4.95-4.92 (m, 1H),3.03-2.94 (m, 2H).

Compound I-178

The title compound was prepared following general procedure B, except2-amino-4-(methylsulfonyl)butanoic acid was the amine reactant. Thecrude material was purified via silica gel chromatography utilizing a0-10% methanol/dichloromethane gradient to deliver the desired compound,Compound I-178 (6 mg, 14% yield) as a solid.

H¹ NMR (400 MHz, CD₃OD) δ 8.78 (d, 1H), 8.29 (d, 1H), 7.57 (s, 1H),7.29-7.23 (m, 1H), 7.10-7.04 (m, 1H), 7.03 (t, 1H), 6.91 (d, 1H), 6.89(t, 1H), 5.98 (s, 2H), 5.24 (dd, 1H), 3.38-3.25 (m, 1H), 3.22-3.16 (m,1H), 2.29 (s, 3H), 2.67-2.58 (m, 1H), 2.47-2.38 (m, 1H).

Compound I-72

This compound was prepared following the procedure described above forCompound I-71, except the reaction solvent was THF and the work up wascarried out with DCM and brine (22 mg, 31%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.06 (d, 1H), 8.23 (d, 1H), 7.48 (s, 1H),7.33-7.27 (m, 1H), 7.23-7.17 (m, 2H), 7.08-7.03 (m, 1H), 6.77-6.73 (m,1H), 5.86 (s, 2H), 4.33-4.24 (m, 2H), 4.11-4.03 (m, 2H), 3.60-3.55 (m,1H), 3.14-3.07 (m, 2H), 2.85-2.78 (m, 2H).

Compound I-103

The title compound was prepared following general procedure B, exceptD-leucine was the amine reactant. The crude material was purified viasilica gel chromatography utilizing a 0-10% methanol/dichloromethanegradient to deliver the desired compound, Compound I-103 (18 mg, 46%yield) as a solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 12.67 (bs, 1H), 9.07 (d, 1H), 8.23 (d, 1H),8.04 (d, 1H), 7.39 (s, 1H), 7.28 (dd, 1H), 7.20-7.14 (m, 1H), 7.14 (d,1H), 7.07 (t, 1H), 6.84 (t, 1H), 5.89-5.80 (m, 2H), 4.74-4.64 (m, 1H),1.86-1.79 (m, 1H), 1.70-1.58 (m, 2H), 0.90 (d, 3H), 0.67 (d, 3H).

Compound I-148

The title compound was prepared following general procedure B, except(R)-2-amino-3,3-dimethylbutanoic acid was the amine reactant. The crudematerial was purified via silica gel chromatography utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-148 (33 mg, 83% yield) as a solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 12.84 (br. s, 1H), 9.09 (d, 1H), 8.27 (d,1H), 7.43-7.27 (m, 2H), 7.33-7.27 (m, 1H), 7.18 (t, 1H), 7.15 (d, 1H),7.08 (t, 1H), 6.85 (t, 1H), 5.85 (s, 2H), 4.58 (d, 1H), 0.96 (s, 9H).

Compound I-151

The title compound was prepared following general procedure B, except(S)-2-amino-3,3-dimethylbutanoic acid was the amine reactant. The crudematerial was purified via silica gel chromatography utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-151 (22 mg, 59% yield) as a solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 12.84 (br. s, 1H), 9.09 (d, 1H), 8.27 (d,1H), 7.43-7.27 (m, 2H), 7.33-7.27 (m, 1H), 7.18 (t, 1H), 7.15 (d, 1H),7.08 (t, 1H), 6.85 (t, 1H), 5.85 (s, 2H), 4.58 (d, 1H), 0.96 (s, 9H).

Compound I-137

The title compound was prepared following general procedure B, exceptN-methyl-L-leucine was the amine reactant. The crude material waspurified via silica gel chromatography utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-137 (14 mg, 36% yield) as a solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.79 (d, 1H), 8.34 (d, 1H), 7.52 (s, 1H), 7.27(dd, 1H), 7.10-7.01 (m, 2H), 6.95-6.90 (m, 2H), 5.98 (s, 2H), 5.57-5.47(m, 1H), 3.44 (d, 3H), 2.03-1.98 (m, 2H), 1.74-1.51 (m, 1H), 1.00 (d,3H), 0.98 (d, 3H).

Compound I-115

The title compound was prepared following general procedure B, exceptethyl 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-3-carboxylate (4equiv.) was the amine reactant, and the reaction was run in THF. Theworkup was carried out in dichloromethane and brine. The crude materialwas purified via silica gel chromatography utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-115 (42 mg, 37% yield) as a solid.

¹H-NMR (400 MHz, CDCl3) δ 8.47 (d, 1H), 8.35 (d, 1H), 7.40 (s, 1H),7.21-7.16 (m, 1H), 7.01 (t, 1H), 6.95 (t, 1H), 6.84 (t, 1H), 6.65 (d,1H), 5.98 (s, 2H), 5.35 (s, 2H), 4.59 (t, 2H), 4.48 (q, 2H), 4.30 (t,2H), 1.44 (t, 3H).

Compound I-16

Intermediate 1 (0.030 g, 0.080 mmol) was diluted with THF (2.0 ml) thencharged with3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine(0.031 g, 0.161 mmol). Reaction was heated to 50° C. and stirred for 1hour. At this time, the LC/MS did not show product forming—therefore, atthis time TEA (0.056 ml, 0.401 mmol) was added and the resultingreaction mixture was heated to 80° C. overnight. In the morning, cleanreaction was detected by LC/MS. The crude reaction was concentrated andpurified using SiO₂ chromatography employing a 0-50% (7:1 ACN/MeOH) inDCM gradient to deliver the desired material as a white solid (32 mg,72%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.08 (d, 1H), 8.43 (d, 1H), 7.62 (s, 1H),7.30 (dd, 1H), 7.23 (d, 1H), 7.19 (t, 1H), 7.07 (t, 1H), 6.81 (t, 1H),5.89 (s, 2H), 5.24 (s, 2H), 4.33-4.25 (m, 4H).

Compound I-112

The title compound was prepared following general procedure B, exceptD-serine was the amine reactant and the reaction was run in THF/water.The crude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-112 (4 mg, 15% yield) as a solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.78 (d, 1H), 8.27 (dd, 1H), 7.51 (s, 1H),7.29-7.23 (m, 1H), 7.07 (t, 1H), 7.02 (t, 1H), 6.92-6.91 (m, 1H), 6.88(t, 1H), 5.97 (s, 2H), 5.13 (t, 1H), 4.09 (d, 2H).

Compound I-86

The title compound was prepared following general procedure B, exceptD-valine was the amine reactant and the reaction was run in THF/water.The crude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-86 (2 mg, 7% yield) as a solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.80 (d, 1H), 8.32 (d, 1H), 7.57 (s, 1H),7.31-7.25 (m, 1H), 7.10-7.02 (m, 2H), 6.95 (s, 1H), 6.95-6.91 (m, 1H),6.00 (s, 2H), 4.85 (d, 1H), 2.45-2.36 (m, 1H), 1.11 (d, 3H), 1.10 (d,3H).

Compound I-88

The title compound was prepared following general procedure B, exceptL-leucine was the amine reactant and the reaction was run in THF/water.The crude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-88 (3 mg, 10% yield) as a solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 12.67 (bs, 1H), 9.07 (d, 1H), 8.23 (d, 1H),8.04 (d, 1H), 7.39 (s, 1H), 7.28 (dd, 1H), 7.20-7.14 (m, 1H), 7.14 (d,1H), 7.07 (t, 1H), 6.84 (t, 1H), 5.89-5.80 (m, 2H), 4.74-4.64 (m, 1H),1.86-1.79 (m, 1H), 1.70-1.58 (m, 2H), 0.90 (d, 3H), 0.67 (d, 3H).

Compound I-67

The title compound was prepared following general procedure B, exceptglycine was the amine reactant and the reaction was run in THF/water.The crude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-67 (8 mg, 33% yield) as a solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 12.72 (bs, 1H), 9.07 (d, 1H), 8.25 (d, 1H),8.14 (bs, 1H), 7.45 (s, 1H), 7.32-7.27 (m, 1H), 7.21-7.16 (m, 1H), 7.16(d, 1H), 7.07 (t, 1H), 6.80 (t, 1H), 5.86 (s, 2H), 4.15 (d, 2H).

Compound I-69

The title compound was prepared following general procedure B, exceptL-valine was the amine reactant and the reaction was run in THF/water.The crude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-69 (24 mg, 66% yield) as a solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.80 (d, 1H), 8.32 (d, 1H), 7.57 (s, 1H),7.31-7.25 (m, 1H), 7.10-7.02 (m, 2H), 6.95 (s, 1H), 6.95-6.91 (m, 1H),6.00 (s, 2H), 4.85 (d, 1H), 2.45-2.36 (m, 1H), 1.11 (d, 3H), 1.10 (d,3H).

Compound I-89

The title compound was prepared following general procedure B, exceptN-methyl-L-valine was the amine reactant and the reaction was run inTHF/water. The crude material was purified via reverse phase HPLC todeliver the desired compound, Compound I-89 (22 mg, 76% yield) as asolid.

¹H-NMR (400 MHz, CD₃OD) δ 8.74 (d, 1H), 8.17 (d, 1H), 7.41 (s, 1H),7.27-7.22 (m, 1H), 7.09-6.98 (m, 2H), 6.87 (d, 1H), 6.81 (t, 1H), 5.93(s, 2H), 4.71 (d, 1H), 3.31 (s, 3H), 2.51-2.43 (m, 1H), 1.14 (d, 3H),0.96 (d, 3H).

Compound I-79

The title compound was prepared following general procedure B, exceptthiomorpholine 1,1-dioxide was the amine reactant and the reaction wasrun in THF/water. The workup was carried out in dichloromethane andbrine. The crude material was purified via reverse phase HPLC to deliverthe desired compound, Compound I-79 (4 mg, 16% yield).

¹H-NMR (400 MHz, CDCl3) δ 8.47-8.45 (m, 1H), 8.33 (d, 1H), 7.24 (s, 1H),7.19 (dd, 1H), 7.02 (t, 1H), 6.96 (t, 1H), 6.84 (t, 1H), 6.57 (d, 1H),5.94 (s, 2H), 4.36 (dd, 2H), 3.19 (dd, 2H).

Compound I-68

The title compound was prepared following general procedure B, exceptL-serine was the amine reactant and the reaction was run in THF/water.The crude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-68 (12 mg, 48% yield) as a solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.78 (d, 1H), 8.27 (dd, 1H), 7.51 (s, 1H),7.29-7.23 (m, 1H), 7.07 (t, 1H), 7.02 (t, 1H), 6.92-6.91 (m, 1H), 6.88(t, 1H), 5.97 (s, 2H), 5.13 (t, 1H), 4.09 (d, 2H).

Compound I-65

The title compound was prepared following general procedure B, excepttert-butylamine (50 equiv.) was the amine reactant and the reaction washeated to 60° C. for 48 h as a solution in THF. The reaction wasconcentrated in vacuo, and the crude material was purified via silicagel chromatography utilizing a 0-30% (7:1 acetonitrile/methanol) indichloromethane gradient to deliver the desired compound, Compound I-65(19 mg, 96% yield) as a solid ¹H-NMR (400 MHz, CDCl3) δ 8.45 (d, 1H),8.14 (d, 1H), 7.40 (bs, 1H), 7.21-7.16 (m, 1H), 7.03-6.91 (m, 3H), 6.61(d, 1H), 5.93 (s, 2H), 1.58 (s, 9H).

Compound I-113

This compound was prepared by treating Compound I-115 with LiOH.H₂O in a2:1:1 solvent mixture of THF:MeOH:water. Once decarboxylation wascomplete, the reaction was acidified using 1N HCl, and was thenextracted (3 times) with dichloromethane. The organic portions werecombined, dried (Na₂SO₄), filtered, and then concentrated. The crudematerial was purified via silica gel chromatography using a 0-10% MeOHin dichloromethane gradient to deliver the title compound, CompoundI-113, as a white solid (5 mg, 5%).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.07 (d, 1H), 8.50 (s, 1H), 8.41 (d, 1H),7.61 (s, 1H), 7.32-7.28 (m, 1H), 7.24 (d, 1H), 7.19 (t, 1H), 7.07 (t,1H), 6.81 (t, 1H), 5.89 (s, 2H), 5.14 (s, 2H), 4.28-4.16 (m, 4H).

Compound I-174

The title compound was prepared following general procedure B, except3-aminopropanoic acid was the amine reactant, and contents were heatedto 110° C. for 14 h as a solution in THF/water (10:1). The crudematerial was purified via reverse-phase prep-HPLC to deliver the desiredcompound, Compound I-174 (17 mg, 56%) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.80 (br. s., 1H), 8.17 (br. s., 1H), 7.55(s, 1H), 7.29 (d, 1H), 7.01-7.15 (m, 2H), 6.95 (br. s., 1H), 6.91 (d,1H), 6.00 (br. s., 2H), 3.96 (t, 2H), 2.77 (t, 2H).

Compound I-169

The title compound was prepared following general procedure B, except3-(methylamino)propanoic acid was the amine reactant, and contents wereheated to 110° C. for 4 h as a solution in THF/water (10:1). Reactionwas concentrated in vacuo, and the crude material was purified viareverse phase HPLC to deliver the desired compound, Compound I-169 (14mg, 56% yield) as a solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.71 (d, 1H), 8.17 (d, 1H), 7.48 (s, 1H),7.19 (d, 1H), 6.89-7.05 (m, 2H), 6.84 (d, 2H), 5.90 (s, 2H), 4.05 (t,2H), 3.42 (d, 3H), 2.71 (t, 2H).

Compound I-170

The title compound was prepared following general procedure B, except2-methyl-3-(methylamino)propanoic acid was the amine reactant, andcontents were heated to 110° C. for 18 h as a solution in THF/water(10:1). Reaction was concentrated in vacuo, and the crude material waspurified via reverse phase HPLC to deliver the desired compound,Compound I-170 (13 mg, 51% yield) as a solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.68 (d, 1H), 8.09 (d, 1H), 7.38 (s, 1H),7.14-7.21 (m, 1H), 6.90-7.02 (m, 2H), 6.76-6.83 (m, 2H), 5.87 (s, 2H),4.01 (dd, 1H), 3.77 (dd, 1H), 3.34 (d, 3H), 2.92 (m, 1H), 1.14 (d, 3H).

Compound I-171

The title compound was prepared following general procedure B, except(R)-2-(aminomethyl)-3-methylbutanoic acid was the amine reactant, andcontents were heated to 110° C. for 18 h as a solution in THF/water(10:1). Reaction was concentrated in vacuo, methanol was added, and thecrude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-171 (15 mg, 57% yield) as a solid.

¹H NMR (500 MHz, METHANOL-d₄) δ ppm 8.86 (d, 1H), 8.29 (d, 1H), 7.60 (s,1H), 7.33 (d, 1H), 7.06-7.17 (m, 2H), 6.99-7.05 (m, 1H), 6.95 (d, 1H),6.04 (s, 2H), 3.93-4.08 (m, 2H), 2.71 (ddd, 1H), 2.10 (dq, 1H),1.07-1.20 (m, 6H).

Compound I-173

The title compound was prepared following general procedure B, except(S)-2-(aminomethyl)-3-methylbutanoic acid was the amine reactant, andcontents were heated to 110° C. for 18 h as a solution in THF/water(10:1). Reaction was concentrated in vacuo, and the crude material waspurified via reverse phase HPLC to deliver the desired compound,Compound I-173 (18 mg, 68% yield) as a solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.84 (d, 1H), 8.25 (d, 1H), 7.56 (s, 1H),7.31 (d, 1H), 7.04-7.15 (m, 2H), 6.96-7.01 (m, 1H), 6.93 (d, 1H), 6.01(s, 2H), 3.91-4.04 (m, 2H), 2.71 (dt, 1H), 2.04-2.14 (m, 1H), 1.14 (d,3H), 1.10 (d, 3H).

Compound I-181

The title compound was prepared following general procedure B, except(R)-3-amino-4-methylpentanoic acid was the amine reactant, and contentswere heated to 100° C. for 18 h as a solution in THF/water (10:1).Reaction was concentrated in vacuo, and the crude material was purifiedvia reverse phase HPLC to deliver the desired compound, Compound I-181(7 mg, 21% yield).

¹H NMR (500 MHz, CD₃OD) δ ppm 8.85 (d, 1H), 8.29 (d, 1H), 7.65 (s, 1H),7.30-7.37 (m, 1H), 7.07-7.16 (m, 2H), 6.98-7.03 (m, 2H), 6.05 (s, 2H),4.91-4.96 (m, 1H), 2.71-2.86 (m, 2H), 2.05-2.13 (m, 1H), 1.08 (dd, 6H).

Compound I-182

The title compound was prepared following general procedure B, except(S)-3-amino-4-methylpentanoic acid was the amine reactant, and contentswere heated to 100° C. for 18 h as a solution in THF/water (10:1).Reaction was concentrated in vacuo, and the crude material was purifiedvia reverse phase HPLC to deliver the desired compound, Compound I-182(7 mg, 24% yield).

¹H NMR (500 MHz, CD₃OD) δ ppm 8.79-8.85 (m, 1H), 8.23-8.28 (m, 1H), 7.63(d, 1H), 7.30 (br. s., 1H), 7.03-7.15 (m, 2H), 6.94-7.02 (m, 2H), 6.03(br. s., 2H), 2.66-2.85 (m, 2H), 2.01-2.13 (m, 2H), 1.00-1.10 (m, 6H).

Compound I-195 and Compound I-196

The title compounds were prepared following general procedure B, except4-methyl-3-(methylamino)pentanoic acid was the amine reactant, andcontents were heated at 100° C. for 18 h as a solution in THF/water(10:1). Reaction was concentrated in vacuo, and the crude material waspurified via reverse phase HPLC to deliver two compounds, Compound I-195(5 mg, 16% yield), and Compound I-196 (12 mg, 41% yield).

¹H NMR for Compound I-195 (500 MHz, CD₃OD) δ ppm 8.82 (d, 1H), 8.28 (d,1H), 7.57 (s, 1H), 7.29-7.34 (m, 1H), 7.05-7.15 (m, 2H), 6.93-6.98 (m,2H), 6.02 (s, 2H), 2.92 (m, 2H), 2.75-2.82 (m, 3H), 2.10-2.19 (m, 2H),1.13 (d, 3H) 1.00 (d, 3H).

¹H NMR for Compound I-196 (500 MHz, CD₃OD) δ ppm 8.83 (d, 1H), 8.21 (d,1H), 7.64 (s, 1H), 7.29-7.35 (m, 1H), 7.05-7.14 (m, 2H), 6.95-7.01 (m,2H), 6.03 (s, 2H), 3.27 (s, 3H).

Compound I-202

The title compound was prepared in 3 steps:

Step 1: Synthesis of (R)-methyl3-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)-4-methylpentanoate

To a stirred solution of Compound I-181 in ether/methanol (3:1) wasadded TMS-diazomethane (2 equiv.) slowly at 23° C. The mixture wasstirred for 30 min, and the solvent was removed in vacuo. The crudematerial was purified via silica gel chromatography to deliver thedesired intermediate, (R)-methyl3-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)-4-methylpentanoate(58 mg, 56% yield).

Step 2: Synthesis of (R)-methyl3-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)(methyl)amino)-4-methylpentanoate

To a 0° C. solution of (R)-methyl3-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)-4-methylpentanoatein DMF was added sodium hydride (1.2 equiv.) followed by iodomethane(1.1 equiv.). The mixture was stirred and warmed to 23° C. Reactionquenched with water, and layers separated. Aqueous layer extracted withdichloromethane, and organic layer dried, filtered, and concentrated.Residue taken onto the next step without further purification.

Step 3: Synthesis of Compound I-202

To a stirred solution of (R)-methyl3-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)(methyl)amino)-4-methylpentanoatein THF/water/methanol (3:1:1) was added solid sodium hydroxide (3equiv.). Contents stirred at 23° C. for 18 h. Solvent was removed invacuo, and the crude material was purified via reverse phase HPLC todeliver Compound I-202 (0.5 mg, 12% yield) as a solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.83 (d, 1H), 8.29 (d, 1H), 7.58 (s, 1H),7.32 (dd, 2H), 7.06-7.15 (m, 1H), 6.93-6.99 (m, 2H), 6.02 (s, 2H), 2.90(dd, 2H), 2.75-2.82 (m, 3H), 2.14 (m, 2H), 1.13 (d, 3H), 1.00 (d, 3H).

Compound I-206

The title compound was prepared following general procedure B, except3-amino-2,2-difluoropropanoic acid was the amine reactant, and contentswere heated to 110° C. for 18 h as a solution in dioxane/water (10:1).Reaction was concentrated in vacuo, methanol was added, and the crudematerial was purified via reverse phase HPLC to deliver the desiredcompound, Compound I-206 (20 mg, 22% yield).

¹H NMR (500 MHz, CD₃OD) δ ppm 8.78 (d, 1H), 8.22 (d, 1H), 7.61 (s, 1H),7.25-7.31 (m, 1H), 7.07-7.12 (m, 1H), 7.05 (t, 1H), 6.96 (d, 1H), 6.89(t, 1H), 6.00 (s, 2H), 4.35 (t, 2H).

Compound I-251

The title compound was prepared following general procedure B, except(S)-3-amino-4,4-dimethylpentanoic acid was the amine reactant, andcontents were heated to 110° C. for 18 h as a solution in dioxane/water(10:1). Reaction was concentrated in vacuo, methanol was added, and thecrude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-251 (15 mg, 44% yield).

¹H NMR (500 MHz, CD₃OD) δ ppm 8.83 (d, 1H), 8.26 (d, 1H), 7.63 (s, 1H),7.29-7.35 (m, 1H), 7.06-7.16 (m, 2H), 7.02 (d, 1H), 6.95-7.00 (m, 1H),6.04 (s, 2H), 2.82-2.88 (m, 1H), 2.72 (dd, 2H), 1.08 (s, 9H).

Compound I-266

A solution of 5,5-difluoropiperidine-2-carboxylic acid (2.5-3.0equivalents), triethylamine (8.0-10 equivalents) and Intermediate 1 wasstirred in dioxane/water (2:1 ratio) at 100° C. until completeconsumption of starting material by LC/MS, following general procedureB. The solution was poured into 1N HCl and extracted withdichloromethane. The organic phases were dried over sodium sulfate,filtered and concentrated in vacuo. Purification by silica gelchromatography (3-8% methanol/dichloromethane gradient) yielded thedesired compound, Compound I-266, (29 mg, combined yield from 2experiments) as an off-white solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.46 (d, 1H), 8.25 (d, 1H), 7.36 (s, 1H), 7.20(app. q, 1H), 7.03 (app. t, 1H), 6.96 (app. t, 1H), 6.69 (app. t, 1H),6.58 (d, 1H), 6.22 (d, 1H), 6.08 (d, 1H), 5.95 (m, 1H), 4.59 (m, 1H),3.53 (dd, 1H), 2.37 (br. d, 1H), 2.08 (m, 2H), 1.57 (m, 1H).

Compound I-263

The title compound was prepared in 4 steps:

Step 1: Synthesis of tert-butyl 4,4-difluoropiperidine-1-carboxylate

A suspension of 4,4-difluoropiperidine hydrochloride and triethylamine(2.2 equivalents) in dichloromethane was added to a solution ofdi-tert-butyl dicarbonate (1.1 equivalents) in dichloromethane slowlyvia a pipet (note: gas evolution was observed). The reaction was stirredat ambient temperature until complete consumption of starting materialas indicated by NMR. The reaction mixture was diluted withdichloromethane and washed with half-saturated ammonium chloridesolution. The organic layer was dried over sodium sulfate, filtered, andthe solvent was removed in vacuo. Purification by silica gelchromatography (2% ethyl acetate/hexane) yielded tert-butyl4,4-difluoropiperidine-1-carboxylate (73%).

Step 2: Synthesis of1-(tert-butoxycarbonyl)-4,4-difluoropiperidine-2-carboxylic acid

A 0.5 M solution of tert-butyl 4,4-difluoropiperidine-1-carboxylate,tetramethylethylenediamine (TMEDA, 1.0 equivalent) in anhydrous ether at−78° C. was treated dropwise with sec-butylithium (1.2 equivalents) andstirred for 2 hours. Carbon dioxide gas was then introduced via bubblingfor 2 min. The reaction was stirred at −78° C. for 10 min, warmed toambient temperature and stirred for an additional hour. The resultingmixture was then quenched with water, acidified to pH 2 with 1N HCl andextracted with ethyl acetate. The combined organic layers were driedover sodium sulfate, filtered, and the solvent was removed in vacuo.Purification by silica gel chromatography (20-50% ethyl acetate/hexanegradient) yielded1-(tert-butoxycarbonyl)-4,4-difluoropiperidine-2-carboxylic acid (87%).

Step 3: Synthesis of 2-carboxy-4,4-difluoropiperidinium trifluoroacetate

A solution of trifluoroacetic acid (20 equivalents) and1-(tert-butoxycarbonyl)-4,4-difluoropiperidine-2-carboxylic acid wasstirred in dichloromethane at ambient temperature until completeconsumption of starting material by LC/MS. The reaction mixture wasconcentrated in vacuo to afford 2-carboxy-4,4-difluoropiperidiniumtrifluoroacetate (Intermediate WW) as a sticky pale orange solid (>99%)which was used without further manipulation.

Step 4: Synthesis of Compound I-263

The title compound was prepared following general procedure B, except2-carboxy-4,4-difluoropiperidinium trifluoroacetate (2.4 equiv.) was theamine reactant, and contents were heated to 100° C. The crude materialwas purified via silica gel chromatography utilizing a 2-7%methanol/dichloromethane gradient to deliver the desired compound,Compound I-263 (26 mg, 56% yield) as an off-white solid.

¹H-NMR (400 MHz, acetone-d₆) δ 8.88 (s, 1H), 8.30 (d, 1H), 7.50 (s, 1H),7.31 (app. q, 1H), 7.14 (app. t, 1H), 7.08 (app. t, 1H), 7.01 (s, 1H),6.90 (app. t, 1H), 5.96 (s, 2H), 5.70 (br. d, 1H), 4.69 (br. d, 1H),3.68 (app. t, 1H), 2.84 (m, 1H), 2.52 (m, 1H), 2.23 (m, 2H).

Compound I-247

A mixture of Intermediate-1 (26.0 mg),(2S)-3-methyl-2-(methylamino)pentanoic acid (0.030 g, 3 equiv andtriethylamine (0.096 ml, 10 equiv) in a 10:1 mixture of THF/Water washeated at 85° C. for 16 hrs, following procedure B. The reaction wascooled, the solvent removed, and the resulting crude purified viapreparative reverse-phase HPLC to afford the desired product, CompoundI-247 as a solid (2.4 mg, 7.2% yield). d ¹H NMR (500 MHz, CD₃OD) δ 8.80(d, 1H), 8.32 (d, 1H), 7.51 (s, 1H), 7.26-7.32 (m, 1H), 7.02-7.13 (m,2H), 6.92-6.95 (m, 1H), 6.91 (d, 1H), 5.99 (s, 2H), 5.49 (s, 1H), 3.44(d, 3H), 2.03 (s, 1H), 1.03 (t, 3H), 0.98 (dd, 2H), 0.85-0.92 (m, 3H).

Compound I-255

A mixture of Intermediate-1 (36.0 mg),4-isopropylpiperidine-4-carboxylic acid (3 equiv.), and TEA (10 equiv.),in a 10:1 mixture of THF/Water was heated at 90° C. for 3 hrs, followinggeneral procedure B. The reaction was cooled, the solvent removed, andthe resulting crude to afford the desired product, Compound I-255, as awhite solid (22 mg 49% yield)

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.49 (d, 1H), 8.35 (d, 1H), 7.64(s, 1H), 7.48 (s, 1H), 7.20-7.25 (m, 1H), 7.05 (s, 1H), 7.01-7.05 (m,3H), 6.67 (d, 1H), 5.98 (s, 2H), 4.80 (d, 2H), 3.72-3.79 (m, 1H), 3.23(t, 2H), 2.35 (d, 3H), 1.80-1.92 (m, 2H), 1.62 (td, 2H), 1.41 (t, 1H),0.97 (d, 6H)

Compound I-254

A mixture of Intermediate-1 (35.0 mg), 4 2-(piperidin-4-yl)benzoic acid(3 equiv.), and TEA (10 equiv.), in a 10:1 mixture of THF/Water washeated at 90° C. for 2 hrs. The reaction mixture was cooled, the solventremoved, and the mixture treated with 1N HCl and the resulting crude waspurified via preparative reverse-phase HPLC to afford the desiredproduct, Compound I-254, as a white solid (1 mg, 2% yield).

¹H NMR (500 MHz, CDCl₃) δ ppm 8.45 (d, 1H), 8.22 (d, 1H), 7.99 (dd, 1H),7.51-7.56 (m, 1H), 7.39-7.44 (m, 2H), 7.32 (t, 1H), 7.17-7.24 (m, 1H),6.95-7.09 (m, 2H), 6.86-6.93 (m, 1H), 6.61 (s, 1H), 5.98 (s, 2H), 4.90(br. s., 2H), 3.94 (br. s., 1H), 3.21 (t, 2H), 2.03-2.09 (m, 2H),1.80-1.90 (m, 2H)

Compound I-256

A mixture of Intermediate 1 (20.0 mg),4-(tert-pentyl)piperidine-4-carboxylic acid (3 equiv., as the TFA salt),and TEA (10 equiv.), in a 10:1 mixture of THF/Water was heated at 90° C.for 2 hrs. The reaction was cooled, the organic solvent removed, 1N HCladded, and the resulting precipitate was filtered to afford the desiredproduct, Compound I-256, as a white solid (13.4 mg, 47% yield).

¹H NMR (500 MHz, CDCl₃) δ ppm: 8.45 (d, 1H), 8.17 (d, 1H), 7.29 (s, 1H),7.15-7.22 (m, 1H), 6.99-7.07 (m, 1H), 6.96 (t, 1H), 6.85 (t, 1H), 6.58(d, 1H), 5.97 (s, 2H), 4.69 (d, 2H), 3.04 (t, 2H), 2.25 (d, 2H), 1.71(td, 2H), 1.35-1.45 (m, 2H), 0.90-0.95 (m, 6H), 0.87 (t, 3H)

Compound I-258

To a solution of(S)-2-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)-3-methylbutanoicacid (Compound I-69, 0.040 g, 0.088 mmol) in DCM (1.8 ml) was added CDI(0.043 g, 0.264 mmol). The reaction was heated at 45° C. for 60 minutes.After this, DBU (0.013 ml, 0.088 mmol) and cyclopropanesulfonamide(0.053 g, 0.440 mmol) were added. Reaction was continued for anadditional 40 minutes at the same temperature, until it was deemed to becomplete. At this time, the reaction was quenched with 1N HCl. Thelayers were separated and the aqueous portion was extracted two timeswith DCM. The organic portions were combined, dried (Na₂SO₄), filtered,and concentrated. The crude material was purified using silicachromatography 0-10% MeOH/DCM gradient to afford the desired compound,Compound I-258, as a white solid (10.8 mg, 80% yield).

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm: 9.93 (br. s., 1H), 8.46 (d, 1H),8.21 (d, 1H), 7.32 (s, 1H), 7.21-7.25 (m, 1H), 6.99-7.09 (m, 2H),6.91-6.97 (m, 1H). 6.61 (d, 1H), 6.03-6.08 (m, 1H), 5.93-5.99 (m, 1H),5.45 (d, 1H), 4.35 (t, 1H), 2.77-2.88 (m, 1H), 2.52-2.62 (m, 1H),1.12-1.15 (m, 6H), 1.05-1.07 (m, 2H), 0.88-0.90 (m, 2H).

Compound I-259

To a solution of Compound I-88 in dichloromethane was added CDI (3equiv.). Reaction heated to 45° C. for 30 min, after which DBU (1equiv.) and methanesulfonamide (5 equiv.) were added. Reaction washeated for an additional 40 min until reaction was complete. At thistime, the reaction was quenched with 1N hydrochloric acid solution. Thelayers were separated, and the aqueous portion was extracted withdichloromethane (2×). The organic portions were combined, dried(Na₂SO₄), filtered, and concentrated. The crude material was purifiedvia silica gel chromatography utilizing a 0-10% methanol/dichloromethanegradient to deliver the desired compound, Compound I-259 (15.8 mg, 44%yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 10.14 (br. s., 1H), 8.47 (d, 1H), 8.22 (d,1H), 7.33 (s, 1H), 7.21-7.26 (m, 1H), 6.99-7.08 (m, 2H), 6.91-6.96 (m,1H), 6.63 (d, 1H), 5.96-6.09 (m, 2H), 5.3 (br. s., 1H) 4.51-4.60 (m,1H), 3.06-3.11 (m, 3H), 1.90-2.00 (m, 1H), 1.71-1.87 (m, 2H), 1.05 (d,3H), 0.96-0.99 (m, 3H).

Compound I-261

To a solution of Compound I-103 in dichloromethane was added CDI (3equiv.). Reaction was heated to 45° C. for 1.5 h, after which DBU (1equiv.) and cyclopropanesulfonamide (5 equiv.) were added. Reaction washeated for an additional 40 minutes, until reaction was complete. Thereaction was quenched with 1N hydrochloric acid solution, the layerswere separated, and the aqueous portion was extracted withdichloromethane (2×). The organic portions were combined, dried(Na₂SO₄), filtered, and concentrated. The crude material was purifiedusing silica gel chromatography utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-261 (40 mg, 80% yield) as a solid.

¹H NMR (500 MHz, CDCl₃) δ ppm: 10.20 (br. s., 1H), 8.47 (s, 1H), 8.22(br. s., 1H), 7.35 (s, 1H), 7.17-7.26 (m, 1H), 6.91-7.09 (m, 3H), 6.64(s, 1H), 5.92-6.09 (m, 2H), 5.39 (br. s., 1H), 4.59-4.70 (m, 1H),2.76-2.89 (m, 1H), 2.50-2.65 (m, 1H), 1.95 (dt, 1H), 1.69-1.86 (m, 2H),1.04 (d, 2H), 0.98 (d, 3H), 0.85-0.95 (m, 3H), 0.74-0.83 (m, 1H).

Compound I-264

A mixture of Intermediate-1 (38.8 mg), 2,2-dimethylthiomorpholine1,1-dioxide, (3 equiv.), and TEA (10 equiv.), in a 10:1 mixture ofTHF/Water was heated at 90° C. for 3 hrs, following general procedure B.The reaction was cooled, poured into a 1:1 mixture of 1N HCl and DCM,the organics extracted (three times) combined, dried, purified by silicachromatography utilizing a 0-10% methanol/dichloromethane gradient todeliver the desired compound, Compound I-264 (40 mg, 77% yield) as awhite solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.48 (d, 1H), 8.31 (d, 1H), 7.26 (s, 1H),7.22 (q, 1H), 7.02-7.07 (m, 1H), 6.99 (t, 1H), 6.86-6.91 (m, 1H), 6.59(d, 1H), 5.97 (s, 2H), 4.41 (br.s., 2H), 4.09 (br.s., 2H), 3.26 (t, 2H),1.43 (s, 6H).

Compound I-270

A mixture of Intermediate-1 (313 mg),(S)-4-methyl-3-(methylamino)pentanoic acid (3 equiv.), and TEA (10equiv.), in a 10:1 mixture of THF/Water was heated at 85° C. for 3 hrs,following procedure B. The reaction was cooled, poured into a 1:1mixture of 1N HCl and DCM, the organics extracted (three times)combined, dried, purified via silica gel chromatography utilizing a0-10% methanol/dichloromethane gradient to deliver the desired compound,Compound I-270 (56 mg, 14% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.48-8.53 (m, 1H), 8.31 (br. s., 1H), 7.39(s, 1H), 7.20-7.26 (m, 1H), 7.13 (t, 1H), 6.99-7.05 (m, 2H), 6.66 (br.s., 1H), 5.86-5.94 (m, 2H), 3.19 (d, 3H), 2.85 (dd, 1H), 2.60-2.73 (m,1H), 1.93-2.05 (m, 1H), 1.26 (s, 1H), 0.93 (d, 3H), 1.08 (d, 3H).

Compound I-271

A mixture of Intermediate 1 (313 mg),(1R,5S,6R)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (3 equiv.), andTEA (10 equiv.), in a 10:1 mixture of THF/Water was heated at 85° C. for3 hrs, following general procedure B. The reaction was cooled, pouredinto a 1:1 mixture of 1N HCl and DCM, the organics extracted (threetimes) combined, dried, purified via silica gel chromatography utilizinga 0-10% methanol/dichloromethane gradient to deliver the desiredcompound, Compound I-271 (22 mg, 33% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ ppm: 8.49 (d, 1H), 8.35 (d, 1H), 7.45 (br. s.,1H), 7.23 (td, 1H), 7.05 (d, 1H), 7.01 (d, 2H), 6.63 (d, 1H), 5.97 (s,2H), 4.32 (d, 2H), 3.95 (d, 2H), 2.40 (br. s., 2H, 1.65 (t, 1H), 0.97(d, 1H).

Compound I-268

The title compound was prepared in 2 steps:

Step 1: Synthesis of 2-carboxy-5,5-dimethylpiperidinium trifluoroacetate

2-carboxy-5,5-dimethylpiperidinium trifluoroacetate was prepared as awhite solid following the procedure for the synthesis of2-carboxy-4,4-difluoropiperidinium trifluoroacetate, as described in thepreparation of Compound I-263, with the exception of using3,3-dimethylpiperidine hydrochloride in step 1.

Step 2: Synthesis of Compound I-268

The title compound was prepared following general procedure B, except2-carboxy-5,5-dimethylpiperidinium trifluoroacetate was the aminereactant, and contents were heated to 100° C. The resulting solution waspoured into water and acidified to pH 3 with aqueous 1N hydrochloricacid solution. The resulting precipitate was collected by vacuumfiltration, washed with HCl solution (pH 3) and ether to deliver thedesired compound, Compound I-268 (38 mg, 62% yield) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 13.0 (br. s, 1H), 9.10 (d, 1H), 8.33 (d,1H), 7.50 (s, 1H), 7.33 (app. q, 1H), 7.22 (m, 2H), 7.10 (app. t, 1H),6.85 (app. t, 1H), 5.89 (s, 2H), 5.38 (m, 1H), 3.99 (m, 1H), 3.03 (m,1H), 2.11 (m, 1H), 2.01 (m, 1H), 1.44 (br. d, 1H), 1.32 (td, 1H), 0.97(s, 3H), 0.95 (s, 3H).

Compound I-245

A solution of methyl 2-(4-aminotetrahydro-2H-pyran-4-yl)acetatehydrochloride (3.0 equivalents), triethylamine (10 equivalents) andIntermediate 1 was stirred in dioxane/water (2:1 ratio) at 100° C. untilcomplete consumption of starting material by LC/MS, following generalprocedure B. The solution was poured into water and acidified to pH 3with 1N HCl and extracted with dichloromethane. The organic phases weredried over sodium sulfate, filtered and concentrated in vacuo.Purification by reverse-phase HPLC (20-65% acetonitrile in water with0.1% trifluoroacetic acid, 20 minute gradient) yielded Compound I-245(8.8 mg, 13%) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.82 (d, 1H), 8.31 (d, 1H), 7.53 (s, 1H), 7.30(app. q, 1H), 7.09 (m, 1H), 7.05 (app. t, 1H), 7.01 (d, 1H), 6.97 (app.t, 1H), 6.00 (s, 2H), 3.82 (dt, 2H), 3.74 (td, 2H), 3.20 (s, 2H), 2.65(br. d, 2H), 2.06 (m, 2H).

Compound I-155

The title compound was prepared following general procedure B, except(R)-pyrrolidin-2-ylmethanol was the amine reactant, and contents wereheated to 40° C. for 18 min as a solution in THF. The reaction wasdiluted with ethyl acetate and washed with water and brine. The organicphase was dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude material was purified via silica gel chromatography utilizing a20-60% ethyl acetate/hexanes gradient to deliver the desired compound,Compound I-155 (11 mg, 44% yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.43 (d, 1H), 8.14 (d, 1H), 7.27 (s, 1H), 7.19(m, 1H), 7.01 (app. t, 1H), 6.97 (app. t, 1H), 6.89 (app. t, 1H), 6.57(d, 1H), 5.94 (s, 2H), 5.29 (br. s, 1H), 4.52 (m, 1H), 3.88 (m, 2H),3.78 (m, 2H), 2.13 (m, 1H), 2.07-1.92 (m, 2H), 1.79 (m, 1H).

Compound I-160

The title compound was prepared following general procedure B, exceptpiperidin-2-ylmethanol was the amine reactant, and contents were heatedto 55° C. for 4 d as a solution in THF/DMSO (2:1). The reaction wasdiluted with ethyl acetate and washed with water and brine. The organicphase was dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude material was purified via silica gel chromatography utilizing a30-60% ethyl acetate/hexanes gradient to deliver the desired compound,Compound I-160 (9.6 mg, 70% yield) as a clear oil.

¹H-NMR (400 MHz, CDCl₃) δ 8.44 (d, 1H), 8.17 (d, 1H), 7.26 (s, 1H), 7.19(m, 1H), 7.02 (app. t, 1H), 6.97 (app. t, 1H), 6.86 (app. t, 1H), 6.58(d, 1H), 5.97 (d, 1H), 5.93 (d, 1H), 4.81 (m, 1H), 4.25 (m, 1H), 4.14(m, 1H), 3.83 (br. s, 1H), 3.79 (m, 1H), 3.28 (m, 1H), 1.85-1.65 (m,6H).

Compound I-183

The title compound was prepared following general procedure B, excepttert-butyl pyrazolidine-1-carboxylate (1.1 equiv.) was the aminereactant, and contents were heated to 70° C. for 5 d as a solution inTHF/DMSO (4:1). The reaction was poured into water and extracted withethyl acetate. The organic phase was dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude material was purified via silica gelchromatography utilizing a 20% ethyl acetate/hexanes gradient to deliverthe desired compound, Compound I-183 (53 mg, 75% yield).

¹H-NMR (400 MHz, CDCl₃) δ 8.44 (d, 1H), 8.26 (d, 1H), 7.30 (s, 1H), 7.18(m, 1H), 7.01 (app. t, 1H), 6.95 (app. t, 1H), 6.84 (app. t, 1H), 6.56(d, 1H), 5.96 (s, 2H), 4.40-3.60 (br. m, 4H), 2.13 (app. quintet, 2H),1.45 (s, 9H).

Compound I-193

A solution of trifluoroacetic acid (20 equivalents) and Compound I-183was stirred in dichloromethane at ambient temperature until completeconsumption of starting material by LC/MS. The solution was carefullypoured into saturated sodium bicarbonate and dichloromethane. The layerswere separated and the organic layer was dried over sodium sulfate,filtered, and the solvent was removed in vacuo to yield Compound I-193(35 mg, 85%) as a white solid.

¹H-NMR (400 MHz, CDCl3) δ 8.43 (d, 1H), 8.17 (d, 1H), 7.31 (s, 1H), 7.18(m, 1H), 7.01 (app. t, 1H), 6.95 (app. t, 1H), 6.82 (app. t, 1H), 6.57(d, 1H), 5.96 (s, 2H), 4.58 (br. s, 1H), 3.87 (m, 2H), 3.19 (app. t,2H), 2.19 (app. quintet, 2H).

Compound I-213

A solution of ethyl bromoacetate (1.0 equivalent),N,N-diisopropylethylamine (1.5 equivalents) and Compound I-193 wasstirred in dimethylformamide at ambient temperature until completeconsumption of starting material by LC/MS. The solution was diluted withwater and extracted with ethyl acetate. The combined organic layers weredried over sodium sulfate, filtered, and the solvent was removed invacuo. Purification by silica gel chromatography (50% ethylacetate/hexanes) yielded Compound I-213 (20 mg, 59%) as a clear oil.

¹H-NMR (400 MHz, CDCl₃) δ 8.44 (d, 1H), 8.21 (d, 1H), 7.32 (s, 1H), 7.17(m, 1H), 7.01 (app. t, 1H), 6.95 (app. t, 1H), 6.83 (app. t, 1H), 6.57(d, 1H), 5.96 (s, 2H), 4.22 (q, 2H), 3.98 (app. t, 2H), 3.70 (s, 2H),3.28 (app. t, 2H), 2.25 (app. quintet, 2H), 1.28 (t, 3H).

Compound I-216

A solution of sodium hydroxide (3.0 N in water, 8.0 equivalents) andCompound I-213 was stirred in methanol at ambient temperature untilcomplete consumption of starting material by LC/MS. The reaction mixturewas concentrated, diluted with water and neutralized to pH 6-7 byaddition of 1N HCl. Crude product was collected by vacuum filtration andpurification by reverse-phase HPLC (5-95% acetonitrile in water with0.1% trifluoroacetic acid, 20 minute gradient) yielded Compound I-216(13 mg, 72%) as an off-white solid.

¹H-NMR (400 MHz, CD₃OD) δ 9.09 (d, 1H), 8.29 (d, 1H), 7.53 (s, 1H), 7.33(m, 1H), 7.22 (m, 2H), 7.10 (app. t, 1H), 6.84 (app. t, 1H), 5.90 (s,2H), 3.84 (m, 2H), 3.57 (s, 2H), 3.12 (m, 2H), 2.17 (app. quintet, 2H).

Compound I-222

A solution of 2-(pyrrolidin-2-yl)acetic acid hydrochloride (2.3equivalents), triethylamine (10 equivalents) and Intermediate 1 wasstirred in dioxane/water (2:1 ratio) at 100° C. until completeconsumption of starting material by LC/MS following procedure B. Thesolution was diluted with water and neutralized to pH 3 by addition of1N HCl. Resultant solid was collected by filtration and dried in vacuoto yield Compound I-222 (63 mg, 94%).

¹H-NMR (400 MHz, DMSO-d₆) δ 12.3 (s, 1H), 9.11 (d, 1H), 8.24 (d, 1H),7.48 (s, 1H), 7.33 (m, 1H), 7.21 (m, 1H), 7.11 (m, 2H), 6.90 (m, 1H),5.87 (s, 2H), 4.62 (m, 1H), 3.80 (m, 1H), 3.65 (m, 1H), 2.82 (m, 1H),2.39 (m, 1H), 2.12-1.90 (m, 3H), 1.84 (m, 1H).

Compound I-184

Compound was obtained by General Procedure B, starting fromIntermediate 1. Purification by silica gel chromatography (20-50% ethylacetate/hexanes gradient) yielded Compound I-184 (62 mg, 81%) as a clearoil.

¹H-NMR (400 MHz, CDCl3) δ 8.45 (d, 1H), 8.22 (d, 1H), 7.27 (s, 1H), 7.19(m, 1H), 7.02 (app. t, 1H), 6.97 (app. t, 1H), 6.87 (app. t, 1H), 6.59(d, 1H), 5.97 (d, 1H), 5.93 (d, 1H), 4.76 (br. m, 1H), 4.34-3.96 (br. m,3H), 3.96-3.74 (br. m, 2H), 3.50-3.10 (br. m, 4H), 1.49 (s, 9H).

Compound I-211 and Compound I-212

A solution of trifluoroacetic acid (20 equivalents) and Compound I-184was stirred in dichloromethane at ambient temperature until completeconsumption of starting material by LC/MS. The solution was carefullypoured into saturated sodium bicarbonate and extracted withdichloromethane. The combined organic layers were dried over sodiumsulfate, filtered, and the solvent was removed in vacuo. Purification byreverse-phase HPLC (5-75% acetonitrile in water with 0.1%trifluoroacetic acid, 20 minute gradient) yielded two products:

Compound I-211 (17 mg, 28% as TFA salt) as a clear oil. ¹H-NMR (400 MHz,CD₃OD) δ 8.79 (m, 1H), 8.35 (m, 1H), 7.52 (s, 1H), 7.28 (m, 1H), 7.10(m, 1H), 7.04 (m, 1H), 6.90 (m, 1H), 6.85 (m, 1H), 5.97 (s, 2H), 5.08(m, 1H), 4.91 (m, 1H), 4.09 (m, 1H), 4.01 (m, 1H), 3.85 (app. t, 1H),3.71 (app. d, 1H), 3.52 (app. d, 1H), 3.45 (m, 1H), 3.40 (m, 1H).

Compound I-212 (19 mg, 32%) as a clear oil. ¹H-NMR (400 MHz, CD₃OD) δ8.80 (s, 1H), 8.34 (d, 1H), 7.61 (d, 1H), 7.29 (m, 1H), 7.10 (app. t,1H), 7.05 (app. t, 1H), 6.94 (m, 1H), 6.91 (app. t, 1H), 6.00 (s, 2H),5.12-4.98 (m, 1H*), 4.82 (m, 1H), 4.59-4.32 (m, 1H*), 4.17 (m, 1H*),3.93-3.58 (m, 4H*), 3.65-3.33 (m, 1H*). Sets of rotamer peaks (˜0.5Heach) seen for select protons marked with *.

Compound I-150

The title compound was prepared in 3 steps:

Step 1: Synthesis of5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-6-hydroxypyrimidin-4(3H)-one (the preparation of this compound was described in a publishedpatent application, WO2013/101830).

A mixture of1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamide,diethyl 2-fluoromalonate (1 equiv.) and DBU (1 equiv.) in ethanol washeated to 70° C. for 24 h. The mixture was concentrated under vacuum togive an oil. The oil was purified by column chromatography (0 to 20%dichloromethane in methanol) to give5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-6-hydroxypyrimidin-4(3H)-one (145 mg, 100% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.81 (d, 1H), 7.42 (s, 1H), 7.26-7.36 (m,1H) 7.05-7.18 (m, 2H), 6.97 (t, 1H), 6.92 (d, 1H), 5.97 (s, 2H).

Step 2: Synthesis of3-(3-(4,6-dichloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole

A mixture of5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-6-hydroxypyrimidin-4(3H)-one (1 equiv.) and POCl₃ (40 equiv.) was heated to 70° C. for 24 h.The mixture was concentrated under vacuum to give a white solid. It wasdiluted in ethyl acetate and washed with water. The organic layer wasdried, filtered and evaporated to give3-(3-(4,6-dichloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole(61 mg, 38% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.40 (s, 1H) 7.37 (s, 1H) 7.10-7.18 (m,1H) 6.88-7.00 (m, 2H) 6.76 (t, 1H) 6.53 (d, 1H) 5.96 (s, 2H).

Step 3: Synthesis of Compound I-150

A mixture of3-(3-(4,6-dichloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole(1 equiv.), morpholine [1M in THF] (1 equiv.) and Hunig's base (1equiv.) in THF was stirred at 23° C. for 24 h. The mixture was dilutedin ethyl acetate and washed with 1N HCl solution. The organic layer wasdried, filtered and evaporated to give a white solid. The solid waspurified by column chromatography (0-100% ethyl acetate in hexanes) todeliver the desired compound, Compound I-150 (32 mg, 47% yield) as awhite solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.47 (d, 1H), 7.31-7.34 (m, 1H), 7.19-7.26(m, 1H), 7.02-7.09 (m, 1H), 6.99 (t, 1H), 6.84 (t, 1H), 6.59 (d, 1H),6.00 (s, 2H), 3.89-3.96 (m, 4H), 3.81-3.89 (m, 4H).

Compound I-172

This compound was prepared in two steps.

Step 1: Synthesis of3-(3-(4-chloro-5-fluoro-6-methoxypyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole

To a suspension of3-(3-(4,6-dichloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole(1 equiv.) in methanol was added sodium methoxide [0.5 M in methanol] (1equiv.). The mixture was stirred at 23° C. for 4 h. The mixture wastreated with HCl (4.0 M in dioxane, 1 equiv.). The mixture wasconcentrated under vacuum. The resulting solid was dissolved in ethylacetate and washed with brine. The organic layer was dried, filtered andevaporated to give3-(3-(4-chloro-5-fluoro-6-methoxypyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole(42 mg, 85% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.67 (d, 1H), 7.45 (s, 1H), 7.16-7.21 (m,1H), 6.97-7.04 (m, 1H), 6.94 (t, 1H), 6.83 (d, 1H), 6.74 (t, 1H), 5.88(s, 2H), 4.12 (s, 3H).

Step 2: Synthesis of Compound I-172

A mixture of3-(3-(4-chloro-5-fluoro-6-methoxypyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole(1 equiv.), triethylamine (2 equiv.) and morpholine (2 equiv.) in THFwas stirred at 100° C. for 24 h. The mixture was diluted in ethylacetate and washed with water. The organic layer was dried, filtered andevaporated to give an oil. The oil was purified by column chromatography(0-100% ethyl acetate in hexanes) to give a light brown solid. The solidwas rinsed with methanol to deliver the desired compound, Compound I-172(19 mg, 41% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.08 (d, 1H), 7.56 (s, 1H), 7.29-7.36(m, 1H), 7.18-7.26 (m, 2H), 7.09 (t, 1H), 6.72 (t, 1H), 5.92 (s, 2H),4.01 (s, 3H), 3.72 (s, 8H).

Compound I-23

A suspension of2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4 (3H)-one (this intermediate was described in a publishedpatent application, WO2012/3405 A1) in phosphoryl trichloride (75equiv.) was heated to 70° C. for 1 h. The phosphoryl trichloride wasremoved under a stream of nitrogen and the resulting crude intermediatewas dissolved in tetrahydrofuran. Morpholine (30 equiv.) was added, andthe solution was stirred at room temperature until the reaction wascomplete by LC/MS. The solution was poured into saturated aqueousammonium chloride solution and dichloromethane.

The layers were separated and the aqueous layer was extracted withdichloromethane. The organics were washed with saturated aqueous sodiumchloride, dried over magnesium sulfate, filtered, and the solvent wasremoved in vacuo. The residue was suspended in diethyl ether and thenresulting solid was filtered off to deliver the desired compound,Compound I-23 (6.5 mg, 69% yield) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.77 (m, 1H), 8.66 (s, 1H), 7.57 (s, 1H),7.31-7.26 (m, 1H), 7.12-7.02 (m, 2H), 6.94 (m, 1H), 6.84 (t, 1H), 5.99(s, 2H), 3.85-3.81 (m, 8H).

Compound I-24

The title compound was synthesized according to the procedure describedfor Compound I-23, with the exception of using2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl) pyrimidin-4(3H)-one (this intermediate was described in previous patent applicationpublication WO2012/3405 A1) as the starting pyrimidone. The finalresidue was suspended in diethyl ether and then the resulting solid wasfiltered off to deliver the desired compound, Compound I-24 (42 mg,quantitative yield) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.74 (m, 1H), 8.21 (d, 1H), 7.46 (s, 1H),7.27-7.22 (m, 1H), 7.10-6.99 (m, 2H), 6.89 (m, 1H), 6.79 (t, 1H), 6.70(d, 1H), 5.95 (s, 2H), 3.77 (br s, 8H).

Compound I-28

The title compound was synthesized according to the procedure describedfor Compound I-23, with the exception of using5-chloro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4(3H)-one (this intermediate was described in published patentapplication WO2012/3405 A1) as the starting pyrimidone. The finalresidue was suspended in diethyl ether and then resulting solid wasfiltered off to deliver the desired compound, Compound I-28 (7.5 mg, 32%yield) as a solid.

¹H-NMR (400 MHz, CDCl3) δ 8.44 (m, 1H), 8.38 (s, 1H), 7.30 (s, 1H),7.21-7.15 (m, 1H), 7.03-6.98 (s, 1H), 6.95 (t, 1H), 6.82 (t, 1H), 6.57(m, 1H), 5.95 (s, 2H), 3.85-3.81 (m, 8H).

Compound I-29

The title compound was synthesized according to the procedure describedfor Compound I-23, with the exception of using2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile(this intermediate was described in a previous patent applicationpublication, WO2012/3405 A1) as the starting pyrimidone. The finalresidue was suspended in diethyl ether and then resulting solid wasfiltered off to deliver the desired compound, Compound I-29 (18 mg, 84%yield) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.11 (m, 1H), 8.78 (s, 1H), 7.71 (s, 1H),7.36-7.31 (m, 1H), 7.27-7.20 (m, 2H), 7.11 (t, 1H), 6.83 (t, 1H), 5.93(s, 2H), 4.02-4.00 (m, 4H), 3.76-3.74 (m, 4H).

Compound I-73

The title compound was prepared in 2 steps:

Step 1: Synthesis of2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-methoxypyrimidin-4(3H)-one

A solution of1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamide (1equiv.), methyl 3-(dimethylamino)-2-methoxyacrylate (3.1 equiv.), and1,8-diazabicycloundec-7-ene (2 equiv.) was stirred at 100° C. for 6 h.The reaction solution was diluted with dichloromethane and saturatedammonium chloride. The layers were separated and the aqueous layer wasextracted with dichloromethane (2×). The organics were washed withsaturated ammonium chloride and brine, dried over magnesium sulfate,filtered, and the solvent was remove in vacuo. Purification of the crudematerial via silica gel chromatography (0-5% methanol in dichloromethanegradient) provided2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-methoxypyrimidin-4-ol(49 mg, 35% yield) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.77 (d, 1H), 7.58 (s, 1H), 7.38 (s, 1H),7.29-7.24 (m, 1H), 7.10-7.02 (m, 2H), 6.92-6.85 (m, 2H), 5.96 (s, 2H),3.87 (s, 3H).

Step 2: Synthesis of Compound I-73

The title compound was synthesized according to the procedure describedfor Compound I-23, with the exception of using2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-methoxypyrimidin-4(3H)-one as the starting pyrimidone. The final residue was suspended indiethyl ether and then resulting solid was filtered off to deliver thedesired compound, Compound I-73 (50 mg, 86% yield) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.08 (m, 1H), 8.11 (s, 1H), 7.51 (s, 1H),7.35-7.29 (m, 1H), 7.24-7.20 (m, 2H), 7.10 (t, 1H), 6.79 (t, 1H), 5.89(s, 2H), 3.88 (s, 3H), 3.75-3.71 (m, 8H).

Compound I-77

A solution of piperidine-4-carboxylic acid (3 equivalents),triethylamine (10 equivalents), and Intermediate 1 was stirred intetrahydrofuran and water (1:1 ratio) at 100° C. until completeconsumption of starting material by LC/MS, following general procedureB. The solution was diluted with aqueous 1N hydrochloric acid and ethylacetate. The layers were separated and the aqueous layer was extractedwith ethyl acetate and 5:1 dichloromethane/isopropyl alcohol. Theorganics were combined, dried over magnesium sulfate, filtered, and thesolvent was removed in vacuo. Purification by reverse-phase HPLC (5-75%acetonitrile in water with 0.1% triefluoroacetic acid, 20 minutegradient) yielded Compound I-77 (11 mg, 44% yield) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.79 (m, 1H), 8.23 (d, 1H), 7.57 (m, 1H),7.31-7.26 (m, 1H), 7.12-7.03 (m, 2H), 6.96 (m, 1H), 6.90 (t, 1H), 5.99(s, 2H), 4.70 (d, 2H), 3.51-3.45 (m, 2H), 2.79-2.74 (m, 1H), 2.15-2.11(m, 2H), 1.90-1.80 (m, 2H).

Compound I-78

The title compound was prepared following general procedure B, exceptpiperidine-3-carboxylic acid was the amine reactant, and contents wereheated to 90° C. for 1.5 h as a solution in THF/water (1:1). Thesolution was diluted with 1N hydrochloric acid solution and ethylacetate. The layers were separated and the aqueous layer was extractedwith ethyl acetate and 5:1 dichloromethane/isopropyl alcohol. Theorganics were combined, dried over magnesium sulfate, filtered, and thesolvent was removed in vacuo. The crude material was purified viareverse phase HPLC (5-75% acetonitrile in water with 0.1%triefluoroacetic acid, 20 minute gradient) to deliver the desiredcompound, Compound I-78 (7 mg, 28% yield) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.81 (m, 1H), 8.28 (d, 1H), 7.60 (m, 1H),7.33-7.27 (m, 1H), 7.13-7.04 (m, 2H), 6.97-6.92 (m, 2H), 6.01 (s, 2H),4.52 (d, 1H), 4.31-4.26 (m, 1H), 4.00 (dd, 1H), 3.93-3.84 (m, 1H),2.84-2.78 (m, 1H), 2.23-2.12 (m, 1H), 2.04-1.88 (m, 2H), 1.82-1.73 (m,1H).

Compound I-76

The title compound was prepared following general procedure B, exceptpyrrolidine-3-carboxylic acid was the amine reactant, and contents wereheated to 60° C. for 2.5 h as a solution in THF/water (1:1). Thesolution was diluted with 1N hydrochloric acid solution and ethylacetate. The layers were separated and the aqueous layer was extractedwith ethyl acetate and 5:1 dichloromethane/isopropyl alcohol. Theorganics were combined, dried over magnesium sulfate, filtered, and thesolvent was removed in vacuo. The crude material was purified viareverse phase HPLC (5-75% acetonitrile in water with 0.1%triefluoroacetic acid, 20 minute gradient) to deliver the desiredcompound, Compound I-76 (11 mg, 45% yield) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.83 (m, 1H), 8.29-8.27 (m, 1H), 7.63 (s, 1H),7.33-7.29 (m, 1H), 7.13-7.05 (m, 2H), 6.99-6.96 (m, 2H), 6.03 (s, 2H),4.23-4.03 (m, 5H), 2.34 (br s, 2H).

Compound I-92

The title compound was prepared following general procedure B, except2-azabicyclo[2.2.1]heptane-3-carboxylic acid was the amine reactant, andcontents were heated to 90° C. for 16 h as a solution in THF/water(10:1). Upon completion of the reaction, 3N hydrochloric acid solutionwas added and the solvent was removed in vacuo. The crude residue wasbrought up in water and the solid was filtered and rinsed with water todeliver the desired compound, Compound I-92 (12 mg, 47% yield) as abrown solid.

¹H-NMR (400 MHz, CD₃OD) exists as >3 diastereomers S 8.80 (m, 1H),8.25-8.16 (m, 1H), 7.32-7.28 (m, 2H), 7.12-7.03 (m, 2H), 6.97-6.83 (m,2H), 6.00-5.96 (m, 2H), 4.51-4.36 (m, 1H), 2.99-2.90 (m, 1H), 2.25 (d,1H), 1.94-1.57 (m, 6H).

Compound I-100

Sodium hydride (1.0 equivalent) and ethyl 1H-pyrrole-2-carboxylate (1equivalent) were dissolved in tetrahydrofuran. After stirring for 15minutes, 0.5 equivalents of pyrrolidine anion was added to a solution ofIntermediate 1 (1.0 equivalent) in tetrahydrofuran at room temperature.After 5 minutes, an additional 0.5 equivalents of anion was added. Thesolution was stirred at room temperature for 45 minutes, 45° C. for 2hours, and then 65° C. for 15 hours. An additional 1 equivalent ofpyrrole anion was added, and after 1.5 hours at 65° C. the solution wasdiluted with saturated aqueous ammonium chloride solution anddichloromethane. The layers were separated and the aqueous layer wasextracted with dichloromethane. The organics were dried over magnesiumsulfate, filtered, and the solvent was removed in vacuo. Purification bysilica gel chromatography (0-50% ethyl acetate in hexanes) providedCompound I-100 (16 mg, 42% yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.71 (m, 1H), 8.45 (m, 1H), 7.40 (s, 1H),7.33-7.32 (m, 1H), 7.22-7.14 (m, 2H), 7.04-6.95 (m, 2H), 6.84 (t, 1H),6.57 (m, 1H), 6.43-6.41 (m, 1H), 6.00 (s, 2H), 4.23 (q, 2H), 1.25 (t,3H).

Compound I-104

A solution of Compound I-100 (1 equivalent) in tetrahydrofuran,methanol, and water (3:1:1 ratio) was treated with lithium hydroxidehydrate (1.5 equivalents). The solution was stirred at room temperaturefor 45 minutes and 45° C. for 3 hours. The solution was diluted withethyl acetate, aqueous 1N sodium hydroxide, and water. The layers wereseparated and the aqueous layer was acidified with aqueous 1Nhydrochloric acid to pH˜1. The acidified aqueous layer was extractedwith ethyl acetate, dried over magnesium sulfate, filtered, and thesolvent was removed in vacuo. Purification by reverse-phase HPLC (5-75%acetonitrile in water w/0.1% trifluoroacetic acid, 20 minute gradient)provided Compound I-104 (1 mg, 6% yield) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.83 (m, 1H), 8.77 (m, 1H), 7.59 (s, 1H), 7.47(m, 1H), 7.31-7.25 (m, 1H), 7.16-7.03 (m, 3H), 6.94 (m, 1H), 6.87 (t,1H), 6.48-6.46 (m, 1H), 6.00 (s, 2H).

Compound I-119

The title compound was prepared following general procedure B, except1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (as the HCl salt) wasthe amine reactant, and the reaction heated as a solution in THF/water(10:1) for 16 h. The solvent was removed in vacuo and the residuebrought up in water. The solid was filtered off and the filtrate waspurified by reverse-phase HPLC (5-75% acetonitrile in water w/0.1%trifluoroacetic acid, 20 minute gradient) to deliver the desiredcompound, Compound I-119 (20 mg, 48% yield) as a white solid.

1H-NMR (400 MHz, CD₃OD) δ 8.80 (m, 1H), 8.33 (d, 1H), 7.55 (br s, 1H),7.30-7.27 (m, 5H), 7.12-7.03 (m, 2H), 6.93 (s, 1H), 6.89 (t, 1H), 5.99(s, 2H), 5.58 (br s, 1H), 5.21 (d, 1H), 5.10 (d, 1H), 3.42-3.40 (m, 2H).

Compound I-140

This was synthesized according to General Procedure B utilizing1,2,3,4-tetrahydroquinoline-2-carboxylic acid and a 10:1 ratio oftetrahydrofuran:water as solvent. Following consumption of startingmaterial, the solvent was removed in vacuo and the resulting residue waspurified by reverse phase HPLC (5-75% acetonitrile in water w/0.1% TFA,20 minute gradient) to provide Compound I-140 (9 mg, 22% yield) as anorange solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.79 (m, 1H), 8.35 (d, 1H), 7.47 (s, 1H),7.30-7.19 (m, 3H), 7.16-7.02 (m, 4H), 6.90-6.85 (m, 2H), 5.97 (s, 2H),5.04 (t, 1H), 2.85-2.81 (m, 1H), 2.75-2.69 (m, 2H), 1.88-1.80 (m, 1H).

Compound I-120

The title compound was prepared following general procedure B, except(S)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid was the aminereactant, and the reaction was heated to 80° C. for 2 h as a solution inTHF/water (10:1). Following consumption of starting material, thesolvent was removed in vacuo and the resulting residue was brought up inmethanol, the solids were filtered off, and the filtrate was purified byreverse phase HPLC (5-75% acetonitrile in water w/0.1% TFA, 20 minutegradient) to deliver the desired compound, Compound I-120 (27 mg, 65%yield) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.80 (m, 1H), 8.34 (d, 1H), 7.67-7.64 (m, 1H),7.55 (s, 1H), 7.34-7.26 (m, 4H), 7.12-7.03 (m, 2H), 6.91 (t, 1H), 6.87(s, 1H), 6.02 (s, 1H), 5.98 (s, 2H), 4.45-3.37 (m, 1H), 4.13-4.04 (m,1H), 3.26-3.20 (m, 1H), 3.05 (dt, 1H).

Compound I-121

The title compound was prepared following general procedure B, except(R)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid was the aminereactant, and the reaction was heated to 80° C. for 2 h as a solution inTHF/water (10:1). Following consumption of starting material, thesolvent was removed in vacuo and the resulting residue was brought up inmethanol, the solids were filtered off, and the filtrate was purified byreverse-phase HPLC (5-75% acetonitrile in water w/0.1% TFA, 20 minutegradient) to deliver the desired compound, Compound I-121 (17 mg, 62%yield) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.80 (m, 1H), 8.34 (d, 1H), 7.67-7.64 (m, 1H),7.55 (s, 1H), 7.34-7.26 (m, 4H), 7.12-7.03 (m, 2H), 6.91 (t, 1H), 6.87(s, 1H), 6.02 (s, 1H), 5.98 (s, 2H), 4.45-3.37 (m, 1H), 4.13-4.04 (m,1H), 3.26-3.20 (m, 1H), 3.05 (dt, 1H).

Compound I-123

The title compound was prepared following general procedure B, exceptpiperidine-4-carbonitrile was the amine reactant, and the reaction washeated to 80° C. for 2 h as a solution in THF/water (10:1). Followingconsumption of starting material, the reaction solution was diluted withdichloromethane and the solvent was dried over magnesium sulfate. Afterfiltering and removing the solvent in vacuo, the crude material waspurified by silica gel chromatography (0-70% ethyl acetate in hexanes)to deliver the desired compound, Compound I-123 (28 mg, 94% yield) as awhite solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.75 (m, 1H), 8.16 (d, 1H), 7.42 (s, 1H),7.29-7.24 (m, 1H), 7.11-7.06 (m, 1H), 7.02 (t, 1H), 6.90 (m, 1H), 6.80(t, 1H), 5.95 (s, 2H), 4.24-4.18 (m, 2H), 3.76-3.70 (m, 2H), 3.13 (tt,1H), 2.08 (ddd, 2H), 1.96-1.87 (m, 2H).

Compound I-141

The title compound was prepared following general procedure B, except2-aminoacetonitrile (as the HCl salt) was the amine reactant, and thereaction was heated to 90° C. as a solution in THF/water (10:1). Afterstirring for 15 h, an additional two equivalents of 2-aminoacetonitrile(as the HCl salt) was added and the solution was stirred for another 24h at which point the solution was diluted with water and ethyl acetate.The layers were separated and the organic layer was washed with water.The organics were dried over magnesium sulfate, filtered, and thesolvent was removed in vacuo. Methanol was added, and the resultingdesired solid product was filtered off. The methanol filtrate containeddissolved product and was purified by reverse phase HPLC (5-75%acetonitrile in water, 0.1% trifluoroacetic acid, 20 minute gradient) togive additional product, which was combined with the filtered solids todeliver the desired compound, Compound I-141 (11 mg, 35% yield) as a tansolid.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.11 (m, 1H), 8.43 (t, 1H), 8.36 (d, 1H),7.61 (s, 1H), 7.36-7.30 (m, 1H), 7.25-7.20 (m, 2H), 7.11 (t, 1H), 6.86(t, 1H), 5.90 (s, 2H), 4.55 (d, 2H).

Compound I-145

A suspension of sodium azide (1 equivalent), ammonium chloride (1equivalent), and Compound I-141 (1 equivalent) in N,N-dimethylformamidewas heated to 80° C. for 1 hour and then 110° C. for 16 hours.Additional ammonium chloride and sodium azide were added, and after 20hours the solution was diluted with methanol and water. Purification byreverse-phase HPLC (5-75% acetonitrile in water with 0.1%trifluoroacetic acid, 20 minute gradient) provided Compound I-145 (6 mg,43%) as a yellow solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.10 (m, 1H), 8.37 (d, 1H), 7.59 (s, 1H),7.35-7.30 (m, 1H), 7.25-7.20 (m, 2H), 7.10 (t, 1H), 6.81 (t, 1H), 5.90(s, 2H), 3.93-3.91 (m, 4H), 3.28-3.26 (m, 4H), 2.91 (br s, 2H).

Compound I-139

To a 0° C. solution of 2-methylpropan-2-ol (165 equivalents) indichloromethane was added sulfurisocyanatidic chloride (150equivalents). The solution was maintained at 0° C. for 20 minutes, andthen 3 equivalents of the resulting sulfonyl chloride was added to aroom temperature solution of Compound I-4 (1 equivalent) andtriethylamine (3 equivalents) in dichloromethane. The solution wasmaintained at room temperature for 30 minutes, at which point thesolution was diluted with saturated aqueous sodium bicarbonate and ethylacetate. The layers were separated and the aqueous layer was extractedwith ethyl acetate. The organics were combined, dried over magnesiumsulfate, filtered, and the solvent was removed in vacuo. Purification bysilica gel chromatography (hexanes in ethyl acetate) gave Compound I-139(8 mg, quantitative yield) as a tan solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.76 (m, 1H), 8.21 (d, 1H), 7.46 (s, 1H),7.29-7.24 (m, 1H), 7.12-7.07 (m, 1H), 7.02 (t, 1H), 6.91 (m, 1H), 6.80(t, 1H), 5.96 (s, 2H), 4.02-3.99 (m, 4H), 3.49-3.47 (m, 2H), 1.46-1.43(m, 9H).

Compound I-125

To a solution of Compound I-4 (1 equivalent) in dichloromethane wasadded triethylamine (2 equivalents) followed by methanesulfonyl chloride(1.5 equivalents). The solution was stirred at room temperature for 15minutes and then diluted with water and ethyl acetate. The layers wereseparated and the organic layer was washed with water. The organics weredried over magnesium sulfate, filtered, and the solvent was removed invacuo to Compound I-125 (8.5 mg, quantitative yield) as a tan solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.06 (m, 1H), 8.34 (d, 1H), 7.56 (s, 1H),7.32-7.27 (m, 1H), 7.22-7.17 (m, 2H), 7.07 (t, 1H), 6.78 (t, 1H), 5.87(s, 2H), 3.90-3.88 (m, 4H), 3.25-3.22 (m, 4H), 2.88 (s, 3H).

Compound I-146

The title compound was prepared following general procedure B,(1H-tetrazol-5-yl)methanamine (as the HCl salt) was the amine reactant,and the reaction was heated to 90° C. for 3 h as a solution indioxane/water (3:1). After workup, the organics were washed with water,dried over magnesium sulfate, filtered, and the solvent was removed invacuo to deliver the desired compound, Compound I-146 (21 mg, 60% yield)as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.81 (m, 1H), 8.34 (d, 1H), 7.45 (s, 1H),7.32-7.26 (m, 1H), 7.12-7.03 (m, 2H), 6.94-6.90 (m, 2H), 6.00 (s, 2H),5.23 (s, 2H).

Compound I-147

A solution of Compound I-139 (1 equiv.) in dichloromethane andtrifluoroacetic acid (200 equiv.) was stirred at 23° C. for 2 h, atwhich point the solvent was removed in vacuo and the residue was broughtup in methanol. The solid product was filtered off. Purification of thefiltrate by reverse phase HPLC (5-75% acetonitrile in water w/0.1%trifluoroacetic acid, 20 minute gradient) and combining with thepreviously filtered product delivered the desired compound, CompoundI-147 (2.4 mg, 41% yield) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.10 (m, 1H), 8.37 (d, 1H), 7.59 (s, 1H),7.36-7.30 (m, 1H), 7.24-7.20 (m, 2H), 7.10 (t, 1H), 6.88 (s, 2H), 6.81(t, 1H), 5.90 (s, 2H), 3.91-3.89 (m, 4H), 3.11-3.09 (m, 4H).

Compound I-149

The title compound was prepared following general procedure B,isoindoline-1-carboxylic acid was the amine reactant, and the reactionwas heated to 80° C. for 1.5 h as a solution in THF/water (10:1). Uponcompletion by LC/MS, the solvent was removed under a stream of nitrogenand the resulting solid was brought up in methanol and water (5:1). Theresulting solids were filtered off and the filtrate was purified byreverse-phase HPLC (5-75% acetonitrile in water w/0.1% trifluoroaceticacid, 20 minute gradient) to deliver the desired compound, CompoundI-149 (14.5 mg, 54% yield) as a tan solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.13 (br s, 1H), 8.39 (br s, 1H), 7.51 (brs, 2H), 7.45-7.39 (m, 2H), 7.36-7.31 (m, 1H), 7.27-7.21 (m, 1H),7.14-7.05 (m, 2H), 6.96-6.75 (m, 2H), 6.03-5.82 (m, 3H), 5.23-5.07 (m,2H).

Compound I-158

To a solution of Compound I-139 (1 equiv) in methanol was added(diazomethyl)trimethylsilane (˜15 equiv) until the yellow colorpersisted. The solvent was removed under a stream of nitrogen to give anintermediate that was not isolated. Dichloromethane and trifluoroaceticacid (200 equivalents) were added, and after stirring at roomtemperature for 2 hours, the solvent was removed under a stream ofnitrogen. Purification by silica gel chromatography (0-5% methanol indichloromethane) provided Compound I-158 (2.1 mg, 31% yield) as a whitesolid.

¹H-NMR (400 MHz, CD₃OD) δ 8.74 (m, 1H), 8.19 (d, 1H), 7.44 (s, 1H),7.28-7.22 (m, 1H), 7.10-7.05 (m, 1H), 7.01 (t, 1H), 6.90 (m, 1H), 6.78(t, 1H), 5.94 (s, 2H), 4.01-3.98 (m, 4H), 2.66 (s, 3H).

Compound I-177

To a 0° C. solution of Compound I-147 (1 equivalent) and pyridine (100equivalents) in dichloromethane was added acetyl chloride (5equivalents). After five minutes, the solution was warmed to roomtemperature and maintained at that temperature for 1 hour. Additionalacetyl chloride (5 equiv) was added and stirred at room temperature for2.5 hours. The solution was then poured into saturated aqueous ammoniumchloride and dichloromethane. The layers were separated and the aqueouslayer was extracted with dichloromethane. The organics were dried overmagnesium sulfate, filtered, and the solvent was removed in vacuo.Purification by reverse-phase HPLC (5-75% acetonitrile in water w/0.1%trifluoroacetic acid, 20 minute gradient) provided Compound I-177 (7.9mg, 29% yield) as a yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.83 (m, 1H), 8.36 (d, 1H), 7.67 (s, 1H),7.33-7.28 (m, 1H), 7.13-7.04 (m, 2H), 6.97-6.92 (m, 2H), 6.02 (s, 2H),4.22-4.20 (m, 4H), 3.60-3.58 (m, 4H), 2.03 (s, 3H).

Compound I-175

The title compound was prepared following general procedure B,4-(methylsulfonyl)piperidine was the amine reactant, and the reactionwas heated to 80° C. for 1.5 h as a solution in THF. Upon completion byLC/MS, the solution was diluted with ethyl acetate and saturated aqueousammonium chloride. The layers were separated and the organic layer waswashed with additional ammonium chloride solution, dried over magnesiumsulfate, filtered, and the solvent was removed in vacuo to deliver thedesired compound, Compound I-175 (25 mg, 93% yield) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.44 (m, 1H), 8.21 (d, 1H), 7.26 (s, 1H),7.20-7.15 (m, 1H), 7.03-6.96 (m, 1H), 6.95 (t, 1H), 6.82 (t, 1H), 6.57(m, 1H), 5.95 (s, 2H), 4.83 (d, 2H), 3.18-3.05 (m, 3H), 3.07 (s, 3H),2.26 (d, 2H), 1.93 (qd, 2H).

Compound I-192

The title compound was prepared following general procedure B,N-methyl-1-(1H-tetrazol-5-yl)methanamine (as the HCl salt) was the aminereactant, and the reaction was heated to 90° C. for 1.5 h as a solutionin dioxane/water (3:1). Following completion of the reaction as judgedby LC/MS, the solution was diluted with 1 N hydrochloric acid solutionand ethyl acetate. The layers were separated and the aqueous layer wasextracted with dichloromethane. The organics were washed with water,dried over magnesium sulfate, filtered, and the solvent was removed invacuo to deliver the desired compound, Compound I-192 (30 mg, 83%) as awhite solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.11 (m, 1H), 8.34 (d, 1H), 7.44 (s, 1H),7.35-7.30 (m, 1H), 7.23-7.17 (m, 2H), 7.10 (t, 1H), 6.84 (t, 1H), 5.88(s, 2H), 5.21 (s, 2H), 3.35 (m, 3H).

Compound I-201

The title compound was prepared following general procedure B, ethyl2-((cyclopropylmethyl)amino)acetate was the amine reactant, and thereaction was heated to 90° C. for 16 h as a solution in dioxane. Thecrude material was purified via silica gel chromatography (0-70% ethylacetate in hexanes) to deliver the desired compound, Compound I-201 (32mg, 81% yield) as a clear oil.

¹H-NMR (400 MHz, CDCl₃) δ 8.43 (m, 1H), 8.17 (d, 1H), 7.21 (s, 1H),7.19-7.13 (m, 1H), 7.01-6.92 (m, 2H), 6.81 (t, 1H), 6.54 (m, 1H), 5.92(s, 2H), 4.37 (s, 2H), 4.17 (q, 2H), 3.63 (d, 2H), 1.21 (t, 3H),1.15-1.09 (m, 1H), 0.59-0.54 (m, 2H), 0.31-0.26 (m, 2H).

Compound I-203

A solution of Compound I-201 (1 equivalent) in tetrahydrofuran, ethanol,and water (ratio 3:1:1) was treated with lithium hydroxide monohydrate(1.5 equivalents) and stirred at room temperature for 4 hours, at whichpoint the solution was diluted with water and dichloromethane. Thelayers were separated and the aqueous layer was acidified to pH˜1. Theacidified aqueous layer was extracted with dichloromethane, dried overmagnesium sulfate, filtered, and the solvent was removed in vacuo togive Compound I-203 (18.5 mg, 65% yield) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.76 (d, 1H), 8.15 (d, 1H), 7.36 (s, 1H),7.29-7.24 (m, 1H), 7.10-7.01 (m, 2H), 6.86-6.82 (m, 2H), 5.94 (s, 2H),4.47 (s, 2H), 3.96 (d, 2H), 1.22-1.15 (m, 1H), 0.59-0.55 (m, 2H),0.38-0.34 (m, 2H).

Compound I-204

The title compound was prepared following general procedure B,2-(isopropylamino)acetic acid was the amine reactant, and the reactionwas heated to 100° C. for 16 h as a solution in dioxane/water (3:1). Thecrude material was purified via silica gel chromatography (0-10%methanol in dichloromethane) to deliver the desired compound, CompoundI-204 (8 mg, 33% yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.40 (br s, 1H), 8.11 (br s, 1H), 7.22 (s,1H), 7.20-7.15 (m, 1H), 7.20-6.92 (m, 2H), 6.83 (br s, 1H), 6.60 (br s,1H), 5.91 (br s, 2H), 4.75 (br s, 1H), 4.14 (br s, 2H), 1.29 (d, 6H).

Compound I-205

The title compound was prepared following general procedure B, ethyl2-(isobutylamino)acetate was the amine reactant, and the reaction washeated to 90° C. for 44 h as a solution in dioxane. Following completionof the reaction as judged by LC/MS, the solution was diluted with waterand dichloromethane. The layers were separated and the aqueous layer wasextracted with dichloromethane. The organics were dried over magnesiumsulfate, filtered, and the solvent was removed in vacuo. The crudematerial was purified via silica gel chromatography (0-50% ethyl acetatein hexanes) to deliver the desired compound, Compound I-205 (19 mg, 57%yield) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.43 (m, 1H), 8.16 (d, 1H), 7.20-7.14 (m, 2H),7.02-6.98 (m, 1H), 6.94 (t, 1H), 6.81 (t, 1H), 6.54 (m, 1H), 6.54 (m,1H), 5.93 (s, 2H), 4.26 (s, 2H), 4.16 (q, 2H), 3.54 (d, 2H), 2.09-2.03(m, 1H), 1.19 (t, 3H), 0.97 (d, 6H).

Compound I-209

A solution of Compound I-205 (1 equivalent) in tetrahydrofuran, ethanol,and water (ratio 3:1:1) was treated with lithium hydroxide monohydrate(2 equivalents) and stirred at room temperature until completeconsumption of starting material as judged by LC/MS. The solution wasdiluted with water and diethyl ether. The layers were separated and theaqueous layer was acidified to pH˜1. The acidified aqueous layer wasextracted with ethyl acetate, dried over magnesium sulfate, filtered,and the solvent was removed in vacuo to give Compound I-209 (13 mg, 86%yield) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.76 (m, 1H), 8.15 (d, 1H), 7.36 (s, 1H),7.29-7.24 (m, 1H), 7.10-7.01 (m, 2H), 6.86-6.82 (m, 2H), 5.92 (s, 2H),4.38 (s, 2H), 3.61 (d, 2H), 2.15-2.08 (m, 1H), 1.00 (d, 6H).

Compound I-257

The title compound was prepared in 4 steps:

Step 1: Synthesis of(S)-2-(4-methylphenylsulfonamido)-3-(pyridin-2-yl)propanoic acid

A suspension of (S)-2-amino-3-(pyridin-2-yl)propanoic acid,p-toluenesulfonyl chloride (1.2 equiv.) in water was treated with sodiumhydroxide (1N solution, 3 equiv.). The reaction was stirred at 90° C.for 18 h. The resulting mixture was cooled to room temperature,neutralized to pH 6 with 1N HCl solution. Sodium chloride was added tosaturate the solution which was then extracted withdichloromethane/iso-propanol (4:1 v/v). The combined organic phases weredried over sodium sulfate, filtered, and the solvent was removed invacuo to afford(S)-2-(4-methylphenylsulfonamido)-3-(pyridin-2-yl)propanoic acid anoff-white solid (35% yield).

Step 2: Synthesis of(S)-2-(N,4-dimethylphenylsulfonamido)-3-(pyridin-2-yl)propanoic acid

A suspension of(S)-2-(4-methylphenylsulfonamido)-3-(pyridin-2-yl)propanoic acid andmethyl iodide (3.2 equiv.) in 1N aqueous sodium hydroxide solution (4.0equiv.) was heated at 100° C. for 6 h. The resulting mixture was cooledto room temperature, neutralized to pH 6 with 1N HCl solution andextracted with dichloromethane/iso-propanol (4:1 v/v). The combinedorganic phases were dried over sodium sulfate, filtered, and the solventwas removed in vacuo. Purification by silica gel chromatography (20-50%acetonitrile/methanol (7:1) in dichloromethane gradient) yielded(S)-2-(N,4-dimethylphenylsulfonamido)-3-(pyridin-2-yl) propanoic acid asa yellow foam solid (39% yield).

Step 3: Synthesis of (S)-2-(methylamino)-3-(pyridin-2-yl)propanoic acid(as HBr salt)

To (S)-2-(N,4-dimethylphenylsulfonamido)-3-(pyridin-2-yl)propanoic acidwas added HBr (33 wt % in glacial acetic acid, 25 equiv.). The reactionwas stirred at 85° C. for 6 h and then at 60° C. for 3 d. Additionalamount of HBr solution (3.3 equiv.) was added and the resulting mixturewas stirred at 85° C. for 6 h. The reaction was cooled to roomtemperature, diluted with water and washed with ether. The aqueous phasewas concentrated in vacuo to afford crude(S)-2-(methylamino)-3-(pyridin-2-yl)propanoic acid dihydrobromide as athick red oil (>99% yield) which was used in the next step withoutfurther manipulation.

Step 4: Synthesis of Compound I-257

The title compound was prepared following general procedure B, except(S)-2-(methylamino)-3-(pyridin-2-yl)propanoic acid (as the HBr salt) wasthe amine reactant, 1.1 equivalents of Intermediate 1 was used, andcontents were heated to 100° C. The crude material was purified viareverse phase HPLC (20-75% acetonitrile in water with 0.1%trifluoroacetic acid, 20 minute gradient) to deliver the desiredcompound, Compound I-257 (123 mg, 73% yield) as a tan solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.81 (d, 1H), 8.49 (d, 1H), 8.24 (d, 1H), 8.13(app. t, 1H), 7.88 (d, 1H), 7.58 (app. t, 1H), 7.42 (s, 1H), 7.29 (app.q, 1H), 7.11 (m, 1H), 7.06 (app. t, 1H), 6.90 (d, 1H), 6.89 (m, 1H),6.01 (d, 1H), 5.97 (d, 1H), 5.65 (br. m, 1H), 3.88 (dd, 1H), 3.67 (dd,1H), 3.35 (d, 3H).

¹H-NMR (400 MHz, CD₃OD) δ 8.81 (d, 1H), 8.49 (d, 1H), 8.24 (d, 1H), 8.13(app. t, 1H), 7.88 (d, 1H), 7.58 (app. t, 1H), 7.42 (s, 1H), 7.29 (app.q, 1H), 7.11 (m, 1H), 7.06 (app. t, 1H), 6.90 (d, 1H), 6.89 (m, 1H),6.01 (d, 1H), 5.97 (d, 1H), 5.65 (br. m, 1H), 3.88 (dd, 1H), 3.67 (dd,1H), 3.35 (d, 3H).

Compound I-200

The title compound was synthesized in 8 steps:

Step 1: Synthesis of ethyl3-(isoxazol-3-yl)-1H-1,2,4-triazole-5-carboxylate

A suspension of isoxazole-3-carbohydrazide (1 equiv.), ethyl2-amino-2-thioxoacetate (1 equiv.) and ammonium chloride (10 equiv.) inabsolute ethanol in a sealed vial was heated at 110° C. for 7 d. Thecrude mixture was concentrated in vacuo. Water was added and the aqueousphase was extracted with ethyl acetate. The combined organic phases weredried over sodium sulfate, filtered, and the solvent was removed invacuo. Purification via silica gel chromatography (10-20%acetonitrile/methanol (7:1) in dichloromethane gradient) yielded ethyl3-(isoxazol-3-yl)-1H-1,2,4-triazole-5-carboxylate as an orange solid(24% yield).

Step 2: Synthesis of ethyl1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-1,2,4-triazole-3-carboxylate andethyl1-(2-fluorobenzyl)-3-(isoxazol-3-yl)-1H-1,2,4-triazole-5-carboxylate

To ethyl 3-(isoxazol-3-yl)-1H-1,2,4-triazole-5-carboxylate in DMF wasadded sodium hydride (60 wt % in mineral oil, 1.2 equiv.). After 10 min,2-fluorobenzyl bromide (1.2 equiv.) was added and the reaction wasstirred for 2 h. Water was added and the resulting mixture was extractedwith ethyl acetate. The combined organic phases were washed with waterand brine, dried over sodium sulfate, filtered, and the solvent wasremoved in vacuo. Purification via silica gel chromatography (10-40%ethyl acetate/hexanes gradient) yielded ethyl1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-1,2,4-triazole-3-carboxylate andethyl1-(2-fluorobenzyl)-3-(isoxazol-3-yl)-1H-1,2,4-triazole-5-carboxylate(63% yield, 42:58 ratio).

Step 3: Synthesis of1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-1,2,4-triazole-3-carboxylic acidand 1-(2-fluorobenzyl)-3-(isoxazol-3-yl)-1H-1,2,4-triazole-5-carboxylicacid

To a solution of ethyl1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-1,2,4-triazole-3-carboxylate andethyl1-(2-fluorobenzyl)-3-(isoxazol-3-yl)-1H-1,2,4-triazole-5-carboxylate intetrahydrofuran/methanol/water (3:1:1 ratio) was added lithium hydroxidehydrate (1.5 equivalents). After 1 h, water and 1N HCl solution (50:8ratio) were added and the resultant mixture was extracted with ethylacetate. Note: Product was not completely soluble and was collected byvacuum filtration. The aqueous layer was extracted withdichloromethane/iso-propanol (4:1 v/v). The combined organic phases wereconcentrated in vacuo and triturated with ether to give additionalproduct. The combined solids (88%, mixture of regioisomers) were used inthe next step without further manipulation.

Step 4: Synthesis of1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-1,2,4-triazole-3-carbonitrile

To a suspension of1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-1,2,4-triazole-3-carboxylic acidand 1-(2-fluorobenzyl)-3-(isoxazol-3-yl)-1H-1,2,4-triazole-5-carboxylicacid, 2-methylpropan-2-amine (2 equiv.), and triethylamine (2 equiv.) inethyl acetate was added n-propylphosphonic anhydride (T3P, 50 wt %solution in ethyl acetate, 3 equiv.). The resultant yellow solution washeated at 65° C. for 2.5 h. The solvent was removed in vacuo. Phosphoryltrichloride (18 equiv.) was added and the resulting mixtures was stirredat 70° C. for 50 min. The reaction was quenched by carefully pouringinto a mixture of water and ice, neutralized to pH 7 by addition ofsaturated sodium bicarbonate solution and extracted withdichloromethane. The combined organic phases were dried over sodiumsulfate, filtered, and the solvent was removed in vacuo. Purification bysilica gel chromatography (10-60% ethyl acetate/hexanes gradient)yielded1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-1,2,4-triazole-3-carbonitrile(39% yield).

Note: One of the regioisomers decarboxylated to form3-(1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)isoxazole. The structuralassignment is consistent with the nOe's observed. This side-reaction mayhave occurred during the saponification step (Step 3).

Step 5: Synthesis of1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-1,2,4-triazole-3-carboximidamide

A solution of1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-1,2,4-triazole-3-carbonitrile inmethanol was treated sodium methoxide (25 wt % solution in methanol, 5equiv.) and stirred for 1 h. Ammonium chloride (10 equiv.) was added.After 18 h, the reaction mixture was concentrated in vacuo andpartitioned between half-saturated sodium bicarbonate/1N sodiumhydroxide solution (10:1 ratio) and ethyl acetate. The organic phaseswere dried over sodium sulfate, filtered, and the solvent was removed invacuo to afford1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-1,2,4-triazole-3-carboximidamide(>99% yield) which was used without further purification.

Step 6: Synthesis of5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-4 (3H)-one

A suspension of1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-1,2,4-triazole-3-carboximidamidewas treated with sodium (Z)-3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olate(3.0 equiv.) and heated at 90° C. for 1 h. After cooling to ambienttemperature, the reaction mixture was neutralized by addition of HCl(1.25 M solution in ethanol). The resultant pale yellow suspension wasstirred for 5 min and then concentrated in vacuo. The residue waspartitioned between dichloromethane and water and the aqueous layer wasback-extracted with dichloromethane. The combined organic phases weredried over sodium sulfate, filtered, and the solvent was removed invacuo. Purification by silica gel chromatography (5-20%acetonitrile/methanol (7:1) in dichloromethane gradient) yielded5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-1,2,4-triazol-3-yl)-pyrimidin-4(3H)-one (61 mg, 74% yield) as a pale yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.95 (d, 1H), 8.09 (d, 1H), 7.35 (app. q, 1H),7.23 (app. t, 1H), 7.17 (d, 1H), 7.15 (m, 2H), 6.07 (s, 2H).

Step 7: Synthesis of3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)isoxazole

A suspension of5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-4 (3H)-one in phosphoryl trichloride (77 equiv.) was heated to65° C. for 2 h. The reaction mixture was carefully poured into ice andstirred for 20 min. The resultant mixture was basicified to pH 8 byaddition of saturated sodium bicarbonate and extracted withdichloromethane. The combined organic layers were dried over sodiumsulfate, filtered, and the solvent was removed in vacuo to afford3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)isoxazoleas an off-white solid (>99% yield).

Step 8: Synthesis of Compound I-200

The title compound was prepared following general procedure B, except(S)-3-methyl-2-(methylamino)butanoic acid was the amine reactant,3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)isoxazolewas used in place of Intermediate 1, and contents were heated to 100° C.The crude material was purified via silica gel chromatography (20-50%(acetonitrile/methanol=7:1) in dichloromethane gradient) yielded impureproduct. The sample was re-purified by reverse phase HPLC (5-95%acetonitrile in water with 0.1% trifluoroacetic acid, 20 minutegradient) to deliver the desired compound, Compound I-200 (23 mg, 66%over two steps) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.56 (d, 1H), 8.34 (d, 1H), 7.27 (app. q, 1H),7.21 (app. t, 1H), 7.15 (d, 1H), 7.06 (m, 2H), 6.09 (d, 1H), 6.02 (d,1H), 4.27 (d, 1H), 3.07 (d, 3H), 2.55 (m, 1H), 1.10 (d, 3H), 0.95 (d,3H).

Compound I-249

The title compound was prepared following general procedure B, except4-methylpiperidine-4-carboxylic acid (as the HCl salt) was the aminereactant,3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)isoxazole(the synthesis of which is described in the procedure for CompoundI-200) was used in place of Intermediate 1, and contents were heated to100° C. for 19 h. The reaction was cooled and diluted with water, andneutralized with aqueous 1N HCl. The resulting solids were collected viavacuum filtration, washed with water, and dried in vacuo to deliver thedesired compound, Compound I-249 (29 mg, 85% yield) as an off-whitesolid.

¹H-NMR (400 MHz, CDCl3) δ 8.54 (d, 1H), 8.22 (d, 1H), 7.24 (m, 1H), 7.17(d, 1H), 7.07-7.00 (m, 3H), 6.08 (s, 2H), 4.41 (br. d, 2H), 3.38 (app.t, 2H), 2.28 (br. d, 2H), 1.59 (m, 2H), 1.31 (s, 3H).

Compound I-1

The title compound was prepared following general procedure B, exceptpyrrolidine (7 equiv.) was the amine reactant, no triethylamine wasused, and contents were heated to 40° C. for 10 min as a solution inTHF, then at 23° C. for 18 h. The reaction was cooled and diluted withethyl acetate, and washed with water and brine. Solvent was removed invacuo to deliver the desired compound, Compound I-1 (23 mg, 76% yield)as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.08 (d, 1H), 8.20 (d, 1H), 7.52 (s,1H), 7.30-7.40 (m, 1H), 7.18-7.28 (m, 2H), 7.10 (t, 1H), 6.82 (t, 1H),5.89 (s, 2H), 3.65-3.70 (m, 4H), 1.92 (d, 4H).

Compound I-2

The title compound was prepared following general procedure B, exceptpiperidine (7 equiv.) was the amine reactant, no triethylamine was used,and contents were heated to 40° C. for 10 min as a solution in THF, thenat 23° C. for 18 h. The reaction was cooled and diluted with ethylacetate, and washed with water and brine. Solvent was removed in vacuoto deliver the desired compound, Compound I-2 (25 mg, 80% yield) as asolid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.09 (s, 1H), 8.26 (d, 1H), 7.54 (s,1H), 7.32 (s, 2H), 7.20-7.27 (m, 2H), 7.10 (t, 1H), 6.81 (t, 1H), 5.90(s, 2H), 3.74-3.80 (m, 4H), 1.58-1.62 (m, 6H).

Compound I-3

The title compound was prepared following general procedure B, exceptmorpholine (7 equiv.) was the amine reactant, no triethylamine was used,and contents were heated to 40° C. for 10 min as a solution in THF, thenat 23° C. for 18 h. The reaction was cooled and diluted with ethylacetate, and washed with water and brine. Solvent was removed in vacuoto deliver the desired compound, Compound I-3 (24 mg, 76% yield) as asolid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.08 (s, 1H), 8.33 (d, 1H), 7.57 (s,1H), 7.32 (d, 2H), 7.20-7.27 (m, 2H), 7.10 (t, 2H), 6.81 (t, 1H), 5.90(s, 2H), 3.79 (d, 4H), 3.74 (d, 4H).

Compound I-4

The title compound was prepared following general procedure B, exceptpiperazine (7 equiv.) was the amine reactant, no triethylamine was used,and contents were heated to 40° C. for 10 min as a solution in THF, thenat 23° C. for 18 h. The reaction was cooled and diluted with ethylacetate, and washed with water and brine. Solvent was removed in vacuoto deliver the desired compound, Compound I-4 (20 mg, 64% yield) as asolid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.09 (s, 1H), 8.33 (d, 1H), 7.56 (s,1H), 7.32 (s, 1H), 7.20-7.28 (m, 2H), 7.10 (t, 1H), 6.81 (t, 1H), 5.90(s, 2H), 3.78-3.84 (m, 4H), 2.90-3.00 (m, 3H).

Compound I-5

The title compound was prepared following general procedure B, exceptN-methylpiperazine (7 equiv.) was the amine reactant, no triethylaminewas used, and contents were heated to 40° C. for 10 min as a solution inTHF, then at 23° C. for 18 h. The reaction was cooled and diluted withethyl acetate, and washed with water and brine. Solvent was removed invacuo to deliver the desired compound, Compound I-5 (23 mg, 71% yield)as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.09 (s, 1H), 8.31 (d, 1H), 7.56 (s,1H), 7.32 (s, 1H), 7.18-7.27 (m, 2H), 7.10 (t, 1H), 6.80 (s, 1H), 5.90(s, 2H), 3.74-3.81 (m, 4H), 3.25-3.35 (s, 3H), 2.20-2.30 (m, 4H).

Compound I-6

The title compound was prepared following general procedure B, except2-morpholinoethanamine (7 equiv.) was the amine reactant, notriethylamine was used, and contents were heated to 40° C. for 10 min asa solution in THF, then at 23° C. for 18 h. The reaction was cooled anddiluted with ethyl acetate, and washed with water and brine. Solvent wasremoved in vacuo to deliver the desired compound, Compound I-6 (25 mg,72% yield) as a gum.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.09 (d, 1H), 8.17 (d, 1H), 7.59 (s,1H), 7.48 (s, 1H), 7.28-7.38 (m, 1H), 7.17-7.26 (m, 2H), 7.10 (t, 1H),6.86 (t, 1H), 5.88 (s, 2H), 3.56-3.62 (m, 4H), 3.48 (t, 4H), 2.44 (m,2H), 2.29-2.40 (m, 2H).

Compound I-7

The title compound was prepared following general procedure B, exceptN,N-dimethylethane-1,2-diamine (7 equiv.) was the amine reactant, notriethylamine was used, and contents were heated to 40° C. for 10 min asa solution in THF, then at 23° C. for 18 h. The reaction was cooled anddiluted with ethyl acetate, and washed with water and brine. Solvent wasremoved in vacuo to deliver the desired compound, Compound I-7 (24 mg,76% yield) as a gum.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.09 (d, 1H), 8.17 (d, 1H), 7.54 (s,1H), 7.48 (s, 1H), 7.29-7.38 (m, 1H), 7.18-7.27 (m, 2H), 7.11 (t, 1H),6.88 (t, 1H), 5.89 (s, 2H), 3.57 (q, 2H), 2.43-2.49 (m, 2H), 2.19 (s,6H).

Compound I-9

The title compound was prepared following general procedure B, exceptcyclohexylamine (7 equiv.) was the amine reactant, no triethylamine wasused, and contents were heated to 40° C. for 10 min as a solution inTHF, then at 23° C. for 18 h. The reaction was cooled and diluted withethyl acetate, and washed with water and brine. Solvent was removed invacuo to deliver the desired compound, Compound I-9 (20 mg, 62% yield)as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.09 (d, 1H), 8.14 (d, 1H), 7.51 (d,1H), 7.45 (s, 1H), 7.33 (d, 1H), 7.18-7.28 (m, 2H), 7.10 (t, 1H), 6.85(t, 1H), 5.88 (s, 2H), 4.03-4.08 (m, 1H), 1.89-1.92 (m, 2H), 1.72-1.76(m, 2H), 1.63 (d, 2H), 1.32-1.43 (m, 4H).

Compound I-8

The title compound was prepared following general procedure B, exceptdimethylamine (7 equiv.) was the amine reactant, no triethylamine wasused, and contents were heated to 40° C. for 10 min as a solution inTHF, then at 23° C. for 18 h. The reaction was cooled and diluted withethyl acetate, and washed with water and brine. Solvent was removed invacuo to deliver the desired compound, Compound I-8 (19 mg, 67% yield)as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.09 (s, 1H), 8.18 (d, 1H), 7.52 (s,1H), 7.39-7.45 (m, 1H), 7.18-7.27 (m, 2H), 7.10 (t, 1H), 6.82-6.88 (m,1H), 5.90 (s, 2H), 3.24 (d, 6H).

Compound I-11

The title compound was prepared following general procedure B, except2-methylpyrrolidine was the amine reactant, no triethylamine was used,and contents were heated to 40° C. for 10 min as a solution in THF, thenat 23° C. for 18 h. The reaction was cooled and diluted with ethylacetate, and washed with water and brine. Solvent was removed in vacuo,and the crude material was purified via silica gel chromatography,utilizing a 0-10% methanol/dichloromethane gradient to deliver thedesired compound, Compound I-11 (16 mg, 51% yield) as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.09 (d, 1H), 8.21 (d, 1H), 7.49 (s,1H), 7.29-7.38 (m, 1H), 7.17-7.27 (m, 2H), 7.10 (t, 1H), 6.84 (t 1H),5.92 (s, 2H), 4.40-4.48 (m, 1H), 3.75-3.90 (m, 1H), 3.56-3.69 (m, 1H),2.00-2.07 (m, 2H), 1.93 (d, 1H), 1.65-1.73 (m, 1H), 1.23 (d, 3H).

Compound I-10

The title compound was prepared following general procedure B, exceptpiperidin-4-ol was the amine reactant, no triethylamine was used, andcontents were heated to 40° C. for 10 min as a solution in THF, then at23° C. for 18 h. The reaction was cooled and diluted with ethyl acetate,and washed with water and brine. Solvent was removed in vacuo to deliverthe desired compound, Compound I-10 (19 mg, 58% yield) as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.08 (d, 1H), 8.27 (d, 1H), 7.54 (s,1H), 7.21-7.39 (m, 3H), 7.10 (t, 1H), 6.81 (t, 1H), 5.90 (s, 2H),4.78-4.84 (m, 1H), 4.18 (d, 2H), 3.74-3.79 (m, 1H), 3.37-3.47 (m, 2H),1.81-8.89 (m, 2H), 1.40-1.54 (m, 2H).

Compound I-12

The title compound was prepared following general procedure B, excepttert-butyl 4-aminopiperidine-1-carboxylate (1.5 equiv.) was the aminereactant, no triethylamine was used, and contents were heated to 40° C.for 10 min as a solution in THF, then at 23° C. for 18 h. The reactionwas cooled and diluted with ethyl acetate, and washed with water andbrine. Solvent was removed in vacuo, and the crude material was purifiedvia silica gel chromatography, utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-12 (36 mg, 90% yield) as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.04-9.15 (m, 1H), 8.18 (d, 1H),7.53-7.65 (m, 1H), 7.47 (s, 1H), 7.30-7.39 (m, 1H), 7.19-7.27 (m, 2H),7.07-7.16 (m, 1H), 6.85 (t, 1H), 5.83-5.91 (m, 2H), 4.25 (d, 1H), 3.96(d, 2H), 2.87-2.91 (m, 2H), 1.87 (d, 2H), 1.44-1.51 (m, 2H),1.41 (s,9H).

Compound I-13

The title compound was prepared following general procedure B, except(S)-pyrrolidin-2-ylmethanol was the amine reactant, no triethylamine wasused, and contents were heated to 40° C. for 10 min as a solution inTHF, then at 23° C. for 18 h. The reaction was cooled and diluted withethyl acetate, and washed with water and brine. Solvent was removed invacuo, and the crude material was purified via silica gelchromatography, utilizing a 0-10% methanol/dichloromethane gradient todeliver the desired compound, Compound I-13 (18 mg, 55% yield) as asolid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.09 (d, 1H), 8.21 (d, 1H), 7.49 (s,1H), 7.28-7.37 (m, 1H), 7.18-7.26 (m, 2H), 7.10 (t, 1H), 6.83 (t, 1H),5.85-5.93 (m, 2H), 4.86 (t, 1H), 4.32-4.39 (m, 1H), 3.74-3.79 (m, 1H),3.62-3.69 (m, 1H), 3.52-3.59 (m, 1H), 3.44-3.50 (m, 1H), 1.98-2.04 (m,2H), 1.91 (d, 2H).

Compound I-17

The title compound was prepared following general procedure B, except3-methoxypyrrolidine (4 equiv.) was the amine reactant, 4 equivalents oftriethylamine was used, and contents were heated to 40° C. for 1 h as asolution in THF. The reaction was cooled and diluted with ethyl acetate,and washed with water and brine. Solvent was removed in vacuo to deliverthe desired compound, Compound I-17 (12 mg, 61% yield) as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.09 (d, 1H), 8.23 (d, 1H), 7.53 (s,1H), 7.29-7.40 (m, 1H), 7.18-7.28 (m, 2H), 7.10 (t, 1H), 6.82 (t, 1H),5.90 (s, 2H), 4.03-4.12 (m, 1H), 3.70-3.87 (m, 3H), 3.66 (d, 1H), 3.28(s, 3H), 1.96-2.15 (m, 2H).

Compound I-18

The title compound was prepared following general procedure B, exceptpiperidin-3-ol (4 equiv.) was the amine reactant, no triethylamine wasused, and contents were heated to 40° C. for 1 h as a solution in THF.The reaction was cooled and diluted with ethyl acetate, and washed withwater and brine. Solvent was removed in vacuo to deliver the desiredcompound, Compound I-18 (14 mg, 72% yield) as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.09 (d, 1H), 8.25 (d, 1H), 7.53 (s,1H), 7.28-7.39 (m, 1H), 7.17-7.27 (m, 2H), 7.10 (t, 1H), 6.81 (t, 1H),5.90 (s, 2H), 4.97 (d, 1H), 4.18 (d, 1H), 3.56-3.68 (m, 1H), 3.37-3.48(m, 2H), 3.21 (dd, 1H), 1.73-1.96 (m, 2H), 1.43-1.58 (m, 2H).

Compound I-25

The title compound was prepared following general procedure B, excepttert-butyl piperidin-3-ylcarbamate (4 equiv.) was the amine reactant, notriethylamine was used, and contents were heated to 40° C. for 1 h as asolution in THF. The reaction was cooled and diluted with ethyl acetate,and washed with water and brine. Solvent was removed in vacuo, and thecrude material was purified via silica gel chromatography, utilizing a0-10% methanol/dichloromethane gradient to deliver the desired compound,Compound I-25 (25 mg, 66% yield) as a solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.75 (d, 1H), 8.16 (d, 1H), 7.58 (s, 1H),7.23-7.38 (m, 1H), 7.08-7.17 (m, 1H), 7.05 (t, 1H), 6.95 (s, 1H), 6.84(t, 1H), 6.78 (d, 1H), 5.98 (s, 2H), 4.40 (d, 1H), 4.13-4.24 (m, 1H),3.69 (br. s., 1H), 3.56 (d, 1H), 3.35-3.42 (m, 1H), 2.00-2.09 (m, 1H),1.91 (dd, 1H), 1.59-1.72 (m, 2H), 1.45 (s, 9H).

Compound I-26

The title compound was prepared following general procedure B, excepttert-butyl 3-aminoazetidine-1-carboxylate (4 equiv.) was the aminereactant, 2 equivalents of triethylamine was used, and contents wereheated to 40° C. for 1 h as a solution in THF, followed by heating to75° C. until full consumption of starting material was observed on theLC/MS. The reaction was cooled and diluted with ethyl acetate, andwashed with water and brine. Solvent was removed in vacuo, and the crudematerial was purified via silica gel chromatography, utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-26 (24 mg, 67% yield) as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.10 (d, 1H), 8.31 (d, 1H), 8.25 (d,1H), 7.48-7.57 (m, 1H), 7.29-7.38 (m, 1H), 7.15-7.28 (m, 2H), 7.11 (t,1H), 6.85 (t, 1H), 5.89 (s, 2H), 4.76-4.93 (m, 1H), 4.15-4.25 (m, 2H),3.91 (dd, 2H), 1.39 (s, 9H).

Compound I-27

The title compound was prepared following general procedure B, excepttert-butyl 3-aminopiperidine-1-carboxylate (4 equiv.) was the aminereactant, 2 equivalents of triethylamine was used, and contents wereheated to 40° C. for 1 h as a solution in THF, followed by heating to75° C. until full consumption of starting material was observed on theLC/MS. The reaction was cooled and diluted with ethyl acetate, andwashed with water and brine. Solvent was removed in vacuo, and the crudematerial was purified via silica gel chromatography, utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-27 (24 mg, 57% yield) as a solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.78 (d, 1H), 8.15 (d, 1H), 7.58 (s, 1H),7.25-7.33 (m, 1H), 7.08-7.17 (m, 1H), 7.05 (t, 1H), 6.95 (s, 1H), 6.84(t, 1H), 6.78 (d, 1H), 5.98 (s, 2H), 4.40 (d, 1H), 4.18 (d, 1H), 3.69(m, 1H), 3.56 (d, 1H), 3.39 (d, 1H), 1.99-2.08 (m, 1H), 1.91 (dd, 1H),1.57-1.76 (m, 2H), 1.45 (s, 9H).

Compound I-19

The title compound was prepared following general procedure B, except3-methoxypiperidine (4 equiv.) was the amine reactant, 2 equivalents oftriethylamine was used, and contents were heated to 40° C. for 1 h as asolution in THF, followed by heating to 75° C. until full consumption ofstarting material was observed on the LC/MS. The reaction was cooled andfiltered, and the solids were washed with ethyl acetate. The filtratewas collected and washed with water and brine. Solvent was removed invacuo to deliver the desired compound, Compound I-19 (15 mg, 74% yield)as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.06 (d, 1H), 8.23 (d, 1H), 7.49 (s,1H), 7.25-7.35 (m, 1H), 7.13-7.24 (m, 2H), 7.07 (t, 1H), 6.78-6.87 (m,1H), 5.86 (s, 2H), 3.91 (d, 1H), 3.62-3.81 (m, 3H), 3.34 (dd, 1H), 3.23(s, 3H), 1.83-1.94 (m, 1H), 1.72-1.81 (m, 1H), 1.56-1.65 (m, 1H),1.44-1.54 (m, 1H).

Compound I-20

The title compound was prepared following general procedure B, exceptpyrrolidin-3-ol (4 equiv.) was the amine reactant, no triethylamine wasused, and contents were heated to 40° C. for 1 h as a solution in THF.The reaction was cooled and filtered, and the solids were washed withethyl acetate. The filtrate was collected and washed with water andbrine. Solvent was removed in vacuo to deliver the desired compound,Compound I-20 (10 mg, 53% yield) as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.08 (d, 1H), 8.21 (d, 1H), 7.52 (s,1H), 7.29-7.37 (m, 1H), 7.18-7.28 (m, 2H), 7.10 (t, 1H), 6.82 (t, 1H),5.90 (s, 2H), 5.04 (d, 1H), 4.32-4.39 (m, 1H), 3.81 (d, 1H), 3.69-3.77(m, 1H), 3.60-3.68 (m, 1H), 1.96-2.05 (m, 1H), 1.88-1.95 (m, 1H).

Compound I-21

The title compound was prepared following general procedure B, excepttert-butyl azetidin-3-ylcarbamate (4 equiv.) was the amine reactant, notriethylamine was used, and contents were heated to 40° C. for 1 h as asolution in THF. The reaction was cooled and filtered, and the solidswere collected and dried in vacuo to deliver the desired compound,Compound I-21 (30 mg, 79% yield) as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.08 (s, 1H), 8.25 (m, 1H), 7.62-7.66(m, 2H), 7.51 (s, 1H), 7.29-7.34 (m, 1H), 7.15-7.27 (m, 2H), 7.07-7.14(m, 1H), 6.79-6.84 (m, 1H), 5.90 (s, 2H), 4.35-4.44 (m, 2H), 4.01-4.12(m, 2H), 3.84-3.90 (m, 1H), 1.39 (s, 9H).

Compound I-22

The title compound was prepared following general procedure B, except4-methoxypiperidine (4 equiv.) was the amine reactant, no triethylaminewas used, and contents were heated to 40° C. for 1 h as a solution inTHF. The reaction was cooled and diluted with ethyl acetate, and washedwith water and brine. Solvent was removed in vacuo to deliver thedesired compound, Compound I-22 (15 mg, 74% yield) as a solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.05 (d, 1H), 8.25 (d, 1H), 7.51 (s,1H), 7.26-7.31 (m, 1H), 7.14-7.25 (m, 2H), 7.07 (t, 1H), 6.74-6.82 (m,1H), 5.87 (s, 2H), 4.06-4.11 (m, 2H), 3.42-3.50 (m, 2H), 3.25 (s, 3H),1.89-1.95 (m, 2H), 1.46-1.51 (m, 3H).

Compound I-64

The title compound was prepared following general procedure B, except4-methyltetrahydro-2H-pyran-4-amine (as the HCl salt) (5 equiv.) was theamine reactant, 10 equivalents of Hunig's base was used in place oftriethylamine, and contents were heated to 175° C. for 1 h in themicrowave as a solution in THF/DMF (1:1). The reaction was cooled anddiluted with ethyl acetate, and washed with water and brine. Solvent wasremoved in vacuo, and the crude material was purified via silica gelchromatography, utilizing a 5-90% ethyl acetate/hexanes gradient todeliver the desired compound, Compound I-64 (4 mg, 20% yield) as asolid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.74 (s, 1H), 8.05 (d, 1H), 7.19-7.33 (m,2H), 6.97-7.12 (m, 2H), 6.79-6.93 (m, 2H), 5.92 (s, 2H), 3.67-3.81 (m,4H), 2.49 (d, 2H), 1.77-1.91 (m, 2H), 1.63 (s, 3H).

Compound I-101

The title compound was prepared following general procedure B, except4-(tert butoxycarbonyl)piperazine-2-carboxylic acid hydrate (4 equiv.)was the amine reactant, 5 equivalents of triethylamine was used, andcontents were heated to 90° C. for 5 h as a solution in THF/water (9:1).Workup was carried out with ethyl acetate instead of dichloromethane.The crude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-101 (12 mg, 26% yield) as a solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.10 (d, 1H), 8.39 (d, 1H), 7.54 (s,1H), 7.28-7.39 (m, 1H), 7.15-7.25 (m, 2H), 7.11 (t, 1H), 6.85 (t, 1H),5.85-5.97 (m, 2H), 5.17 (br. s., 1H), 4.45 (d, 1H), 4.33 (br. s., 1H),3.91-4.02 (m, 1H), 3.33-3.39 (m, 2H), 3.05-3.17 (m, 1H), 1.41 (s, 9H).

Compound I-163

The title compound was prepared following general procedure B, except4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-4-carboxylic acid (4equiv.) was the amine reactant, 3 equivalents of triethylamine was used,and contents were heated to 175° C. for 10 min as a solution in NMP.Contents were diluted with diethyl ether, and the resulting precipitatewas filtered and collected. The crude material was further purified viareverse phase HPLC to deliver the desired compound, Compound I-163 (5mg, 15% yield) as a solid.

¹H NMR (500 MHz, methanol-d₄) δ ppm 9.03 (d, 1H), 8.82-8.89 (m, 1H),8.58 (s, 1H), 7.58 (s, 1H), 7.28-7.37 (m, 1H), 7.11-7.18 (m, 1H),7.02-7.10 (m, 1H), 6.94 (s, 1H), 6.83-6.92 (m, 1H), 6.01 (s, 2H), 5.12(d, 1H), 5.00 (d, 1H), 4.55-4.64 (m, 1H), 3.43 (dd, 1H), 3.20 (d, 1H).

Compound I-189

The title compound was prepared following general procedure B, except4-ethylpiperidine-4-carboxylic acid (as the HCl salt) was the aminereactant, 4 equivalents of triethylamine was used, and contents wereheated to 40° C. for 18 h as a solution in THF. The reaction wasincomplete, so additional amine reactant (3 equiv.), triethylamine (4equiv.) and DMF (equivalent volume as THF) was introduced into thevessel, and the resulting mixture was heated to 85° C. for 18 h. Thereaction was cooled and diluted with ethyl acetate, and washed withwater and brine. Solvent was removed in vacuo, and the crude materialwas purified via reverse phase HPLC to deliver the desired compound,Compound I-189 as a solid.

¹H NMR (500 MHz, methanol-d₄) δ ppm 8.79 (d, 1H), 8.20 (d, 1H), 7.54 (s,1H), 7.21-7.35 (m, 1H), 7.07-7.13 (m, 1H), 7.05 (t, 1H), 6.95 (d, 1H),6.89 (t, 1H), 5.99 (s, 2H), 4.65 (d, 2H), 3.33-3.43 (m, 2H), 2.32 (d,2H), 1.63-1.68 (m, 2H), 1.55-1.63 (m, 2H), 0.91 (t, 3H).

Compound I-190

The title compound was prepared following general procedure B, except3-methylpiperidine-4-carboxylic acid was the amine reactant, 4equivalents of triethylamine was used, and contents were heated to 40°C. for 18 h as a solution in THF. The reaction was incomplete, soadditional amine reactant (3 equiv.), triethylamine (4 equiv.) and DMF(equivalent volume as THF) was introduced into the vessel, and theresulting mixture was heated to 85° C. for 18 h. The reaction was cooledand diluted with ethyl acetate, and washed with water and brine. Solventwas removed in vacuo, and the crude material was purified via reversephase HPLC to deliver the desired compound, Compound I-190 as a solid.

¹H NMR (500 MHz, methanol-d₄) δ ppm 8.79 (d, 1H), 8.22-8.29 (m, 1H),7.59 (s, 1H), 7.24-7.34 (m, 1H), 7.02-7.15 (m, 2H), 6.96-7.00 (m, 1H),6.93 (t, 1H), 6.01 (m, 2H), 4.76 (d, 1H), 4.58 (d, 1H), 3.70 (dd, 1H),3.52-3.58 (m, 1H), 2.87-2.94 (m, 1H), 2.45-2.54 (m, 1H), 2.00-2.11 (m,1H), 1.90-1.99 (m, 1H), 1.02 (d, 3H).

Compound I-235

The title compound was prepared in 3 steps:

Step 1: Synthesis of2-(1-(2,3-difluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-fluoropyrimidin-4(3H)-one

The above compound was prepared following general procedure A, using1-(isoxazol-3-yl)ethanone in step 1 and 2,3-difluorobenzylhydrazine instep 2.

Step 2: Preparation of3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2,3-difluorobenzyl)-1H-pyrazol-5-yl)isoxazole

A suspension of2-(1-(2,3-difluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-fluoropyrimidin-4(3H)-one in phosphoryl trichloride (47 equiv) was heated at 65° C. for 2hour.

The reaction mixture was carefully poured into ice and stirred for 20min. The resultant mixture was basicified to pH 8 by addition ofsaturated sodium bicarbonate and extracted with dichloromethane. Thecombined organic layers were dried over sodium sulfate, filtered, andthe solvent was removed in vacuo to afford3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2,3-difluorobenzyl)-1H-pyrazol-5-yl)isoxazoleas a light yellow solid which was used in the next step without furthermanipulation.

Step 3: Synthesis of Compound I-235

A solution of (S)-3-methyl-2-(methylamino)butanoic acid (3.0equivalents), triethylamine (10 equivalents). and3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2,3-difluorobenzyl)1H-pyrazol-5-yl)isoxazole was stirred in dioxane/water (2:1 ratio) at100° C. for 23 h, following general procedure B. The solution wasdiluted with water, neutralized to pH 3 by addition of 1N HCl andextracted with dichloromethane. The combined organic layers were driedover sodium sulfate, filtered, and the solvent was removed in vacuo.Purification by silica gel chromatography (0-10% acetonitrile/methanol(7:1) in dichloromethane gradient) yielded Compound I-235 (38 mg, 61%over 2 steps) as an off-white solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.46 (d, 1H), 8.22 (d, 1H), 7.23 (s, 1H), 7.04(dd, 1H), 6.92 (dd 1H), 6.77 (app. t, 1H), 6.58 (d, 1H), 5.99 (d, 1H),5.94 (d, 1H), 4.27 (d, 1H), 3.24 (d, 3H), 2.52 (m, 1H), 1.11 (d, 3H),0.94 (d, 3H).

Compound I-236

The title compound was prepared in 3 steps:

Step 1: Synthesis of5-fluoro-2-(1-(2-fluorobenzyl)-5-(oxazol-2-yl)-1H-pyrazol-3-yl)pyrimidin-4 (3H)-one

The above compound was prepared following general procedure A, using1-(oxazol-2-yl)ethanone in Step 1 and 2-fluorobenzylhydrazine in Step 2.

Step 2: Synthesis of2-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)oxazole

The above compound was prepared following a process analogous to Step 2of the synthesis of Compound I-235, using5-fluoro-2-(1-(2-fluorobenzyl)-5-(oxazol-2-yl)-1H-pyrazol-3-yl)-pyrimidin-4(3H)-one as the starting pyrimidone.

Step 3: Synthesis of Compound I-236

The title compound was prepared following general procedure B, except(S)-3-methyl-2-(methylamino)butanoic acid was the amine reactant,2-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)oxazolewas used in place of Intermediate 1, and contents were heated to 100° C.for 41 h. The crude material was purified via silica gel chromatography(0-20% (acetonitrile/methanol=7:1) in dichloromethane gradient)delivered the desired compound, Compound I-236 (8.9 mg, 49% over twosteps) as an off-white solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.25 (d, 1H), 7.70 (s, 1H), 7.46 (s, 1H), 7.24(s, 1H), 7.21 (m 1H), 7.07-6.95 (m, 3H), 6.11 (d, 1H), 6.04 (d, 1H),4.27 (d, 1H), 3.23 (d, 3H), 2.52 (m, 1H), 1.11 (d, 3H), 0.94 (d, 3H).

Compound I-36

Into a stirred solution of Compound I-12 dissolved in dichloromethanewas added and equivalent volume of trifluoroacetic acid at 23° C.Contents stirred until full consumption of starting material wasobserved via LC/MS. The reaction was diluted with dichloromethane andquenched with saturated sodium bicarbonate solution. The layers wereseparated, and the organic layer was washed with saturated sodiumbicarbonate solution, water, and brine. The organic layer was furtherdried over Na₂SO₄, filtered, and concentrated in vacuo to deliver thedesired compound, Compound I-36 (19.5 mg, 75% yield) as a solid.

¹H NMR (500 MHz, CDCl₃) δ 8.46 (s, 1H), 8.15 (d, 1H), 7.27-7.30 (m, 1H),7.13-7.23 (m, 1H), 7.00-7.09 (m, 1H), 6.91-7.00 (m, 1H), 6.81-6.90 (m,1H), 6.54-6.62 (m, 1H), 5.95 (s, 2H), 5.19 (d, 1H), 4.26-4.40 (m, 1H),3.23-3.35 (m, 2H), 3.03 (br. s, 1H), 2.92 (td, 2H), 2.10-2.20 (m, 2H),1.59-1.77 (m, 2H).

Compound I-37

Into a stirred solution of Compound I-25 dissolved in dichloromethanewas added and equivalent volume of trifluoroacetic acid at 23° C.Contents stirred until full consumption of starting material wasobserved via LC/MS. The reaction was diluted with dichloromethane andquenched with saturated sodium bicarbonate solution. The layers wereseparated, and the organic layer was washed with saturated sodiumbicarbonate solution, water, and brine. The organic layer was furtherdried over Na₂SO₄, filtered, and concentrated in vacuo to deliver thedesired compound, Compound I-37 (14 mg, 79% yield) as a solid.

¹H NMR (500 MHz, CDCl₃) δ 8.45 (d, 1H), 8.16 (d, 1H), 7.30 (s, 1H),7.14-7.23 (m, 1H), 7.00-7.07 (m, 1H), 6.96 (td, 1H), 6.78-6.89 (m, 1H),6.60 (d, 1H), 5.96 (s, 2H), 4.39-4.51 (m, 1H), 4.22-4.36 (m, 1H), 3.25(ddd, 1H), 2.93-3.08 (m, 2H), 1.99-2.11 (m, 1H), 1.83-1.92 (m, 1H),1.59-1.72 (m, 1H), 1.37-1.50 (m, 1H).

Compound I-38

Into a stirred solution of Compound I-26 dissolved in dichloromethanewas added and equivalent volume of trifluoroacetic acid at 23° C.Contents stirred until full consumption of starting material wasobserved via LC/MS. The reaction was diluted with dichloromethane andquenched with saturated sodium bicarbonate solution. The layers wereseparated, and the organic layer was washed with saturated sodiumbicarbonate solution, water, and brine. The organic layer was furtherdried over Na₂SO₄, filtered, and concentrated in vacuo to deliver thedesired compound, Compound I-38 (11 mg, 55% yield) as a solid.

¹H NMR (500 MHz, CDCl₃) δ 8.46 (d, 1H), 8.16-8.22 (m, 1H), 7.30 (m, 1H),7.17-7.25 (m, 2H), 7.00-7.09 (m, 1H), 6.91-6.98 (m, 1H), 6.85 (d, 1H),6.56-6.68 (m, 1H), 5.96-6.03 (m, 1H), 5.95 (s, 2H), 4.94-5.01 (m, 1H),4.39 (t, 2H), 3.99 (dd, 2H).

Compound I-39

Into a stirred solution of Compound I-27 dissolved in dichloromethanewas added and equivalent volume of trifluoroacetic acid at 23° C.Contents stirred until full consumption of starting material wasobserved via LC/MS. The reaction was diluted with dichloromethane andquenched with saturated sodium bicarbonate solution. The layers wereseparated, and the organic layer was washed with saturated sodiumbicarbonate solution, water, and brine. The organic layer was furtherdried over Na₂SO₄, filtered, and concentrated in vacuo to deliver thedesired compound, Compound I-39 (12.2 mg, 69% yield) as a solid.

¹H NMR (500 MHz, CDCl₃) δ 8.45 (d, 1H), 8.13 (d, 1H), 7.35 (s, 1H),7.14-7.24 (m, 1H), 6.99-7.08 (m, 1H), 6.92-6.99 (m, 1H), 6.79-6.89 (m,1H), 6.64 (d, 1H), 5.97 (s, 2H), 5.55 (br. s., 1H), 4.34-4.49 (m, 1H),3.29 (dd, 1H), 2.88-3.01 (m, 1H), 2.79-2.87 (m, 1H), 2.75 (dd, 1H),1.90-2.02 (m, 1H), 1.77-1.88 (m, 1H), 1.58-1.76 (m, 2H).

Compound I-40

Into a stirred solution of Compound I-21 dissolved in dichloromethanewas added and equivalent volume of trifluoroacetic acid at 23° C.Contents stirred until full consumption of starting material wasobserved via LC/MS. The reaction was diluted with dichloromethane andquenched with saturated sodium bicarbonate solution. The layers wereseparated, and the organic layer was washed with saturated sodiumbicarbonate solution, water, and brine. The organic layer was furtherdried over Na₂SO₄, filtered, and concentrated in vacuo to deliver thedesired compound, Compound I-40 (22 mg, 90% yield) as a solid.

¹H NMR (500 MHz, methanol-d₄) δ 8.73 (d, 1H), 8.06 (d, 1H), 7.37 (s,1H), 7.19-7.30 (m, 1H), 7.04-7.11 (m, 1H), 7.00 (t, 1H), 6.86 (d, 1H),6.77 (t, 1H), 5.93 (s, 2H), 4.58 (t, 2H), 4.13 (dd, 2H), 3.98-4.09 (m,1H).

Compound I-133

Into a stirred solution of Compound I-101 dissolved in dichloromethanewas added and equivalent volume of trifluoroacetic acid at 23° C.Contents stirred until full consumption of starting material wasobserved via LC/MS. The mixture was concentrated in vacuo, and theresulting gum was triturated with diethyl ether, filtered, and thesolids were washed with diethyl ether. The solids were collected anddried in vacuo to deliver the desired compound, Compound I-133 (as theTFA salt, 100 mg, 83% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ 9.11 (s, 1H), 8.87 (s, 1H), 8.47 (d, 1H),7.58 (s, 1H), 7.29-7.40 (m, 1H), 7.17-7.27 (m, 2H), 7.11 (t, 1H), 6.83(t, 1H), 5.89 (s, 2H), 5.44-5.49 (m, 1H), 4.59-4.64 (m, 1H), 3.79 (d,1H), 3.41-3.46 (m, 1H), 3.11-3.18 (m, 1H), 3.01-3.12 (m, 1H).

Compound I-30

The title compound was prepared following general procedure B, except2,8-diazaspiro[4.5]decan-3-one (2 equiv.) was the amine reactant, notriethylamine was used, and contents were heated to 40° C. for 2 d as asolution in THF. The reaction was cooled, solvent was removed in vacuo,and the resulting solid was rinsed with 1N HCl solution to deliver thedesired compound, Compound I-30 (57.8 mg, 83% yield) as a white solid.

¹H NMR (500 MHz, METHANOL-d₄) δ ppm 8.86 (s, 1H) 8.36 (d, 1H) 7.71 (s,1H) 7.31-7.37 (m, 1H) 7.13 (dd, 2H) 6.99-7.04 (m, 2H) 6.06 (s, 2H) 4.32(br. s., 2H) 4.13 (br. s., 2H) 3.37 (br. s., 2H) 2.42 (s, 2H) 1.95 (t,4H).

Compound I-42

The title compound was prepared following general procedure B, except2-oxa-7-azaspiro[3.5]nonane oxalate (2 equiv.) was the amine reactant, 8equivalents of triethylamine was used, and contents were heated to 40°C. for 24 h as a solution in NMP. The reaction was cooled, diluted withethyl acetate, and the mixture was rinsed with water. Contents weredried, filtered, and concentrated in vacuo. The crude material waspurified via silica gel chromatography utilizing a 0-80% ethylacetate/hexanes gradient to deliver the desired compound, Compound I-42(42 mg, 52% yield) as a white solid.

¹H NMR (500 MHz, METHANOL-d₄) δ ppm 8.75 (s, 1H) 8.13 (d, 1H) 7.41 (s,1H) 7.20-7.32 (m, 1H) 6.97-7.14 (m, 2H) 6.90 (s, 1H) 6.81 (t, 1H) 5.95(s, 2H) 4.52 (s, 4H) 3.80-3.88 (m, 4H) 1.90-2.05 (m, 4H).

Compound I-43

The title compound was prepared following general procedure B, except8-oxa-2-azaspiro[4.5]decane (2 equiv.) was the amine reactant, notriethylamine was used, and contents were heated to 40° C. for 24 h as asolution in THF. The reaction was cooled and concentrated to yield asolid, which was dissolved in ethyl acetate. The organic layer waswashed with aqueous 1N HCl, dried, filtered, and concentrated in vacuo.The crude material was purified via silica gel chromatography utilizinga 0-100% ethyl acetate/hexanes gradient to deliver the desired compound,Compound I-42 (6.4 mg, 17% yield) as a white solid.

¹H NMR (500 MHz, METHANOL-d₄) δ ppm 8.77 (s, 1H) 8.09 (d, 1H) 7.44 (s,1H) 7.25-7.33 (m, 1H) 7.11 (t, 1H) 7.05 (s, 1H) 6.93 (s, 1H) 6.82 (s,1H) 5.98 (s, 2H) 3.92 (br. s., 2H) 3.71-3.84 (m, 6H) 2.00 (t, 2H)1.64-1.75 (m, 4H).

Compound I-32

The title compound was prepared following general procedure B, except2-oxa-6-azaspiro[3.3]heptane oxalate (2 equiv.) was the amine reactant,6 equivalents of triethylamine was used, and contents were heated to 40°C. for 2 d as a solution in THF. The reaction was cooled andconcentrated to yield a solid, which was dissolved in ethyl acetate. Theorganic layer was washed with 1N HCl solution, dried, filtered, andconcentrated in vacuo to deliver the desired compound, Compound I-32 (19mg, 33% yield) as a white solid.

¹H NMR (500 MHz, METHANOL-d₄) δ ppm 8.83 (s, 1H) 8.24 (br. s, 1H) 7.57(br. s., 1H) 7.29-7.33 (m, 1H) 7.03-7.16 (m, 2H) 6.91-7.01 (m, 2H)5.99-6.05 (m, 2H) 4.28-4.61 (m, 4H) 3.99 (s, 2H) 3.88 (s, 2H).

Compound I-47

The title compound was prepared following general procedure B, except2-oxa-6-azaspiro[3.5]nonane oxalate (2 equiv.) was the amine reactant, 4equivalents of triethylamine was used, and contents were heated to 40°C. for 2 h as a solution in NMP. The reaction was cooled andconcentrated to yield a solid, which was dissolved in ethyl acetate. Theorganic layer was washed with water, dried, filtered, and concentratedin vacuo. The crude material was purified via silica gel chromatographyutilizing a 0-100% ethyl acetate/hexanes gradient to deliver the desiredcompound, Compound I-47 (42.3 mg, 66% yield) as a white solid.

¹H NMR (400 MHz, METHANOL-d₄) δ ppm 8.67-8.76 (m, 1H) 8.12 (d, 1H) 7.40(s, 1H) 7.19-7.28 (m, 1H) 7.02-7.10 (m, 1H) 6.99 (t, 1H) 6.88 (d, 1H)6.79 (t, 1H) 5.89-5.95 (m, 2H) 4.38-4.49 (m, 4H) 4.05-4.10 (m, 2H)3.71-3.79 (m, 2H) 1.92-1.98 (m, 2H) 1.58-1.68 (m, 2H).

Compound I-44

The title compound was prepared following general procedure B, excepttert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2 equiv.) was theamine reactant, no triethylamine was used, and contents were heated to40° C. for 2 d as a solution in THF. The reaction was cooled and dilutedwith ethyl acetate. The organic layer was washed with water, dried,filtered, and concentrated in vacuo. The crude material was purified viasilica gel chromatography utilizing a 0-100% ethyl acetate/hexanesgradient to deliver the desired compound, Compound I-44 (51.6 mg, 67%yield) as a white solid.

¹H NMR (500 MHz, METHANOL-d₄) δ ppm 8.77 (s, 1H) 8.15 (d, 1H) 7.43 (s,1H) 7.23-7.33 (m, 1H) 7.11 (t, 1H) 7.05 (t, 1H) 6.92 (s, 1H) 6.83 (t,1H) 5.97 (s, 2H) 3.79-4.09 (m, 4H) 3.43-3.52 (m, 2H) 3.30 (s, 2H) 1.89(t, 2H) 1.72 (br. s., 4H) 1.49 (s, 9H).

Compound I-45

The title compound was prepared following general procedure B, excepttert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (2 equiv.) was theamine reactant, 1 equivalent of triethylamine was used, and contentswere heated to 40° C. for 2 d as a solution in THF. The reaction wascooled and diluted with ethyl acetate. The organic layer was washed withwater, dried, filtered, and concentrated in vacuo. The crude materialwas purified via silica gel chromatography utilizing a 0-100% ethylacetate/hexanes gradient to deliver the desired compound, Compound I-45(48.3 mg, 64% yield) as a white solid.

¹H NMR (500 MHz, METHANOL-d₄) δ ppm 8.75 (s, 1H) 8.04-8.13 (m, 1H) 7.40(s, 1H) 7.24-7.32 (m, 1H) 7.10 (t, 1H) 7.03 (t, 1H) 6.89 (s, 1H) 6.82(t, 1H) 5.96 (s, 2H) 3.85-3.98 (m, 2H) 3.69-3.82 (m, 2H) 3.49 (br. s.,2H) 3.30-3.43 (m, 4H) 1.48 (d, 9H).

Compound I-61

The title compound was prepared following general procedure B, except3,3-difluoroazetidine (as the HCl salt, 1 equiv.) was the aminereactant, 2 equivalents of Hunig's base was used instead oftriethylamine, and contents were heated to 40° C. for 3 h as a solutionin NMP. The reaction was cooled and diluted with ethyl acetate. Theorganic layer was washed with water, dried, filtered, and concentratedin vacuo. The crude material was purified via silica gel chromatographyutilizing a 0-30% ethyl acetate/hexanes gradient to deliver the desiredcompound, Compound I-61 (37 mg, 71% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.44 (d, 1H) 8.22 (d, 1H) 7.30 (s, 1H)7.14-7.21 (m, 1H) 6.91-7.04 (m, 2H) 6.81 (t, 1H) 6.54-6.59 (m, 1H) 5.95(s, 2H) 4.60-4.71 (m, 4H).

Compound I-62

The title compound was prepared following general procedure B, except4,4-Difluoropiperidine (as the HCl salt, 1 equiv.) was the aminereactant, 2 equivalents of Hunig's base was used instead oftriethylamine, and contents were heated to 40° C. for 3 h as a solutionin NMP. The reaction was cooled and diluted with ethyl acetate. Theorganic layer was washed with water, dried, filtered, and concentratedin vacuo. The crude material was purified via silica gel chromatographyutilizing a 0-30% ethyl acetate/hexanes gradient to deliver the desiredcompound, Compound I-62 (40.4 mg, 71% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.43 (d, 1H) 8.22 (d, 1H) 7.24-7.25 (m,1H) 7.12-7.21 (m, 1H) 6.91-7.04 (m, 2H) 6.82 (t, 1H) 6.56 (d, 1H) 5.94(s, 2H) 3.94-4.02 (m, 4H) 2.04-2.17 (m, 4H).

Compound I-63

The title compound was prepared following general procedure B, except3,3-difluoro-pyrrolidine (as the HCl salt, 1 equiv.) was the aminereactant, 2 equivalents of Hunig's base was used instead oftriethylamine, and contents were heated to 40° C. for 3 h as a solutionin NMP. The reaction was cooled and diluted with ethyl acetate. Theorganic layer was washed with water, dried, filtered, and concentratedin vacuo. The crude material was purified via silica gel chromatographyutilizing a 0-30% ethyl acetate/hexanes gradient to deliver the desiredcompound, Compound I-63 (41.5 mg, 71% yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.43 (d, 1H) 8.19 (d, 1H) 7.29 (s, 1H)7.11-7.22 (m, 1H) 6.90-7.04 (m, 2H) 6.78-6.87 (m, 1H) 6.56 (d, 1H) 5.94(s, 2H) 3.98-4.18 (m, 4H) 2.40-2.54 (m, 2H).

Compound I-166

The title compound was prepared following general procedure B, exceptN-benzylglycine ethyl ester (1 equiv.) was the amine reactant, 2equivalents of triethylamine was used, and contents were heated to 80°C. for 24 h as a solution in THF/water (10:1). The reaction was cooledand diluted with ethyl acetate. The organic layer was washed withsaturated ammonium chloride solution, dried, filtered, and concentratedin vacuo. The crude material was purified via silica gel chromatographyto deliver the desired compound, Compound I-166 (33 mg, 47%) as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.42 (d, 1H) 8.23 (d, 1H) 7.28-7.39 (m,5H) 7.23 (d, 1H) 7.12-7.21 (m, 1H) 6.91-7.05 (m, 2H) 6.83 (t, 1H) 6.53(d, 1H) 5.94 (s, 2H) 5.00 (s, 2H) 4.20-4.24 (m, 2H) 4.14-4.20 (m, 2H)1.21 (t, 3H).

Compound I-167

The title compound was prepared following general procedure B, exceptethyl N-methylaminoacetate (as the HCl salt, 1 equiv.) was the aminereactant, 2 equivalents of triethylamine was used, and contents wereheated to 90° C. for 24 h as a solution in THF. The reaction was cooledand diluted with ethyl acetate and water. The layers were separated, andthe the organic layer was dried, filtered, and concentrated in vacuo.The crude material was purified via silica gel chromatography utilizinga 0-100% ethyl acetate/hexanes gradient to deliver the desired compound,Compound I-167 (77 mg, 79% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.46 (d, 1H) 8.22 (d, 1H) 7.28 (d, 1H)7.15-7.25 (m, 1H) 6.95-7.06 (m, 2H) 6.81-6.89 (m, 1H) 6.58 (d, 1H)5.95-6.00 (m, 2H) 4.35 (s, 2H) 4.23 (q, 2H) 3.43 (d, 3H) 1.25 (t, 3H).

Compound I-176

A mixture of Compound I-167 (70 mg, 1 equiv.) and sodium hydroxide [1.0N aqueous solution] (770 μl, 5 eqiuv.) in THF (385 μl) and MeOH (385 μl)was stirred at rt for 24 h. The mixture was quenched with 1N HCl (5equiv.). The white precipitate formed was collected by filtration,rinsed with a minimal amount of ether and dried to give Compound I-176(52 mg, 79% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.11 (d, 1H) 8.34 (d, 1H) 7.54 (s, 1H)7.30-7.37 (m, 1H) 7.19-7.25 (m, 2H) 7.11 (t, 1H) 6.86 (t, 1H) 5.90 (s,2H) 4.41-4.45 (m, 2H) 3.32 (d, 3H).

Compound I-168

A mixture of Compound I-167 (30 mg, 1 equiv.) and sodium hydroxide [1.0N aqueous solution] (57 μl, 1 equiv) in THF (141 μl) and MeOH (141 μl)was stirred at rt for 24 h. It was treated with 1N HCl (1 equiv.). Themixture was diluted in dichloromethane (100 ml) and washed with water(50 ml). The organic layer was dried, filtered and evaporated to give anoil. The oil was purified by column chromatography (0 to 10% methanol indichloromethane) to give Compound I-168 (10 mg, 36% yield) as a whitesolid.

¹H NMR (400 MHz, METHANOL-d₄) δ ppm 8.74 (d, 1H) 8.20 (d, 1H) 7.33-7.43(m, 5H) 7.22-7.32 (m, 3H) 6.99-7.13 (m, 3H) 6.84 (d, 2H) 5.95 (s, 2H)5.05 (s, 2H).

Compound I-218

A mixture of Compound I-176 (48 mg, 1 equiv.), O-methylhydroxylaminehydrochloride (14 mg, 1.5 equiv), EDC (32 mg, 1.5 equiv.) and DMAP (21mg, 1.5 equiv) in DMF (563 μl) was stirred at rt for 2 h. The mixturewas diluted in ethyl acetate (100 ml) and washed with water (50 ml×3).The organic layer was dried, filtered and evaporated to give an oil. Theoil was purified by column chromatography to give Compound I-218 (26 mg,51% yield) as a white solid.

¹H NMR (500 MHz, METHANOL-d₄) δ ppm 8.63-8.68 (m, 1H) 8.08 (d, 1H) 7.30(s, 1H) 7.13-7.20 (m, 1H) 6.96-7.02 (m, 1H) 6.92 (t, 1H) 6.77 (s, 1H)6.71 (t, 1H) 5.85 (s, 2H) 4.17 (s, 2H) 3.55 (s, 3H) 3.30-3.34 (m, 3H).

Compound I-223

The title compound was prepared following general procedure B, exceptN-methyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)methanamine (as the HCl salt,1 equiv.) was the amine reactant, 4 equivalents of triethylamine wasused, and contents were heated to 85° C. for 24 h as a solution indioxane. The reaction was cooled and diluted with ethyl acetate. Theorganic layer was washed with 1N HCl solution, dried, filtered, andconcentrated in vacuo. The crude material was purified via silica gelchromatography utilizing a 0-100% ethyl acetate/hexanes gradient todeliver the desired compound, Compound I-223 (16.3 mg, 21% yield) as awhite solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.46 (d, 1H) 8.25 (d, 1H) 7.15-7.22 (m,2H) 6.96 (t, 1H) 6.84 (t, 1H) 6.61 (d, 1H) 5.95 (s, 2H) 5.03 (s, 2H)3.52 (d, 3H) 2.38 (s, 3H).

Compound I-14

2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-nitropyrimidin-4-ol(1 equiv.) (this intermediated was in a previous patent: WO2012/3405 A1)(25 mg, 1 equiv.) was treated with POCl₃ (457 μl, 75 equiv.) and stirredat reflux for 1.5 h. Contents were concentrated in vacuo, and residuewas azeotroped with toluene (×2). The residue was re-dissolved in THF(0.7 mL) and treated with morpholine (171 μl, 30 equiv.). The contentswere heated to 40° C., and reaction stirred for 1.5 h. Residue wastransferred to 1:1 mixture of ethyl acetate and water. The layers wereseparated, and the aqueous layer was extracted with ethyl acetate (×3).The organic portions were combined and washed with brine. The mixturewas dried over MgSO₄, filtered, and concentrated in vacuo to deliver thedesired Compound I-14 (30 mg, 97%) as a pale yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.47 (d, 1H), 8.36 (d, 1H), 8.09-8.16 (m, 1H),7.69 (dd, 1H), 7.41 (d, 1H), 7.20 (t, 1H), 6.66-6.70 (m, 1H), 6.45 (d,1H), 6.06 (s, 2H), 3.79-3.86 (m, 4H), 3.74 (m, 4H).

Compound I-15

A solution of Compound I-14 (30 mg, 1 equiv.) in methanol was treatedwith palladium on carbon (7 mg, 10% wt palladium, 0.1 equiv) and placedunder at atmosphere of hydrogen. Contents were stirred for 2 h at 23° C.Contents were filtered over celite, and eluted with methanol. Contentswere concentrated in vacuo, and the crude material was purified viasilica gel chromatography utilizing a 0-70%(acetonitrile:methanol=7:1)/dichloromethane gradient to deliver thedesired Compound I-15 (11.5 mg, 39%) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.43 (d, 1H), 8.36 (d, 1H), 7.35 (d, 1H), 6.80(t, 1H), 6.59-6.53 (m, 1H), 6.49-6.40 (m, 2H), 6.11 (dd, 1H), 5.93-5.82(m, 2H), 3.87-3.76 (m, 4H), 3.72 (d, 4H).

Compound I-70

A solution of Compound I-37 in toluene was treated with ethyl isocyanate(3 equiv.) and heated to 90° C. for 20 min. The resulting precipitateswere filtered and rinsed with toluene. The solids were collected anddried in vacuo to deliver the desired compound, Compound I-70 (7 mg, 36%yield) as a solid.

¹H NMR (500 MHz, DMSO-d₆) δ 9.09 (d, 1H), 8.27 (d, 1H), 7.77 (s, 1H),7.30-7.36 (m, 1H), 7.14-7.27 (m, 2H), 7.07-7.12 (m, 1H), 6.83 (t, 1H),5.94 (d, 1H), 5.91 (s, 2H), 5.76 (t, 1H), 4.17 (d, 1H), 3.94 (d, 1H),3.69 (dt, 1H), 3.52 (t, 1H), 3.22 (dd, 1H), 3.02 (quin, 2H), 1.85 (d,1H), 1.71-1.81 (m, 1H), 1.43-1.62 (m, 2H), 0.97 (t, 3H).

Compound I-71

A solution of Compound I-40 in toluene was treated with ethyl isocyanate(3 equiv.) and heated to 90° C. for 20 min. The resulting precipitateswere filtered and rinsed with toluene. The solids were collected anddried in vacuo to deliver the desired compound, Compound I-71 (3 mg, 16%yield) as a solid.

¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (d, 1H), 8.25 (d, 1H), 7.49-7.55 (m,1H) 7.29-7.37 (m, 1H), 7.19-7.27 (m, 2H), 7.10 (t, 1H), 6.81 (t, 1H),6.52-6.61 (m, 1H), 6.02 (t, 1H), 5.90 (s, 2H), 4.51-4.59 (m, 1H), 4.47(m, 2H), 4.06 (d, 2H), 2.94-3.07 (m, 2H), 0.99 (t, 3H).

Compound I-136

A solution of Compound I-133 in dichloromethane was treated with ethylisocyanate (1.1 equiv.) and triethylamine (2 equiv.), and stirred at 23°C. for 1 h. Solvent removed in vacuo, and residue re-suspended indiethyl ether. The resulting precipitates were filtered and rinsed withdiethyl ether. The solids were collected and dried in vacuo to deliverthe desired compound, Compound I-136 (2.9 mg, 28% yield) as a solid.

¹H NMR (500 MHz, DMSO-d₆) δ 9.09 (s, 1H), 8.26-8.39 (m, 1H), 7.52 (s,1H) 7.32 (m, 1H), 7.17-7.27 (m, 2H), 7.10 (t, 1H), 6.78-6.88 (m, 1H),6.63 (br.s., 1H), 5.90 (m, 2H), 4.90-5.19 (m, 1H) 4.43 (d, 1H), 4.30(br.s., 1H), 3.91 (d, 1H), 3.48 (d, 1H), 3.22 (d, 1H), 2.99-3.05 (m,3H), 1.01 (t, 3H).

Compound I-134

A solution of Compound I-133 in dichloromethane was treated withpropionyl chloride (1.1 equiv.) and triethylamine (2 equiv.), andstirred at 23° C. for 1 h. Solvent removed in vacuo, and residuere-suspended in diethyl ether. The resulting precipitates were filteredand rinsed with diethyl ether. The solids were collected and dried invacuo to deliver the desired compound, Compound I-134 (3.5 mg, 35%yield) as a solid.

¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.40 (d, 1H), 7.49-7.64 (m,1H), 7.28-7.39 (m, 1H), 7.15-7.26 (m, 2H), 7.11 (t, 1H), 6.84 (br. s.,1H), 5.89 (s, 2H), 4.79 (d, 1H), 4.24-4.45 (m, 2H), 3.91 (d, 1H), 3.67(br. s., 1H), 3.58 (d, 1H), 2.87-3.00 (m, 1H), 2.31-2.40 (m, 2H),0.93-1.04 (m, 3H).

Compound I-135

A solution of Compound I-133 in dichloromethane was treated with methylchloroformate (1.1 equiv.) and triethylamine (2 equiv.), and stirred at23° C. for 1 h. Solvent removed in vacuo, and residue re-suspended indiethyl ether. The resulting precipitates were filtered and rinsed withdiethyl ether. The solids were collected purified via reverse phase HPLCto deliver the desired compound, Compound I-135 (3.5 mg, 37% yield) as asolid.

¹H NMR (500 MHz, CD₃OD) δ 8.82 (s, 1H), 8.41 (d, 1H), 7.58 (s, 1H),7.26-7.35 (m, 1H), 7.12 (t, 1H), 7.07 (t, 1H), 6.88-6.97 (m, 2H), 6.01(s, 2H), 5.51 (br. s., 1H), 4.68 (d, 1H), 4.58 (br. s., 1H), 4.09 (d,1H), 3.79-3.95 (m, 1H), 3.76 (s, 3H), 3.52-3.62 (m, 1H), 3.35-3.45 (m,1H).

Compound I-49 and Compound I-50

A solution of 1-methylcyclopropanecarboxylic acid (141 mg, 10 equiv.) indichloromethane (1 mL) was treated with oxalyl chloride (0.11 mL, 9equiv.), and contents were stirred until no more bubbling was observed.The resulting solution was then added portionwise over 5 minutes to acooled (0° C.) solution of5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-pyrimidin-4-amine(1 equiv, 50 mg this intermediate was described in a previous patentapplication publication, WO2012/3405 A1) in dichloromethane (0.35 mL)and pyridine (0.35 mL). The mixture was heated to 60° C. and stirred for24 h. The reaction mixture was diluted with ethyl acetate and washedwith saturated aqueous ammonium chloride solution. The layers wereseparated, and the aqueous layer was extracted with ethyl acetate (×3)and dichloromethane (×1). The organic portions were combined and washedwith brine. The mixture was dried over MgSO₄, filtered, and concentratedin vacuo. The crude material was purified via silica gel chromatographyutilizing a 0-60% ethyl acetate/hexanes gradient to deliver the desiredCompound I-49 (18.5 mg, 30%) as a white solid, along with I-50 (16.2 mg,22%) as a clear oil.

Compound I-49H¹ NMR (400 MHz, CDCl₃) δ 8.57 (d, 1H), 8.43 (d, 1H), 8.01(s, 1H), 7.38 (s, 1H), 7.22-7.13 (m, 1H), 7.00 (t, 1H), 6.98-6.90 (m,1H), 6.78 (t, 1H), 6.57 (d, 1H), 5.99 (s, 2H), 1.48 (s, 3H), 1.38-1.32(m, 2H), 0.79-0.73 (m, 2H).

Compound I-50H¹ NMR (400 MHz, CDCl₃) δ 8.64 (d, 1H), 8.47-8.44 (m, 1H),7.28 (s, 1H), 7.22-7.15 (m, 1H), 7.02 (d, 1H), 6.97 (t, 1H), 6.93-6.87(m, 1H), 6.55-6.53 (m, 1H), 5.95 (s, 2H), 1.53-1.48 (m, 4H), 1.22 (s,6H), 0.85-0.79 (m, 4H).

Compound I-51 and Compound I-52

A solution of5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-pyrimidin-4-amine(1 equiv, this intermediate in a previous patent applicationpublication; WO2012/3405 A1) (see above) (50 mg, 1 equiv.) in THF (0.7mL) was cooled to 0° C. and treated with LiHMDS (0.16 mL, 1.1 equiv., 1Msolution) and stirred for 20 minutes. The reaction was then treated withmethyl chloroformate (44 μL, 4 equiv.). The reaction mixture was stirredat 0° C. for 20 minutes, then warmed to 23° C., over 1 h. The reactionwas diluted with ethyl acetate and quenched with saturated aqueousammonium chloride solution. The layers were separated, and the aqueouslayer was extracted with ethyl acetate (twice) and dichloromethane(three times). The organic portions were combined and washed with brine.The mixture was dried over MgSO₄, filtered, and concentrated in vacuo.The crude material was purified via silica gel chromatography utilizinga 0-100% ethyl acetate/hexanes gradient to deliver the desired CompoundI-51 (5.3 mg, 9%) as an off-white solid, along with Compound I-52 (13.1mg, 20%) as a white solid.

Compound I-51 ¹H-NMR (500 MHz, CDCl₃) δ 8.56 (s, 1H), 8.45 (s, 1H), 7.41(s, 1H), 7.38 (s, 1H), 7.19 (m, 1H), 7.02 (t, 1H), 6.95 (m, 1H), 6.81(m, 1H), 6.61 (s, 1H), 6.00 (s, 2H), 3.87 (s, 3H).

Compound I-52 ¹H-NMR (500 MHz, CDCl₃) δ 8.77 (s., 1H), 8.47 (s, 1H),7.40 (s, 1H), 7.21 (m, 1H), 7.07-6.93 (m, 2H), 6.84 (m, 1H), 6.59 (s,1H), 6.02 (s, 2H), 3.83 (s, 6H).

Compound I-144

In a small vial, Compound I-58 (0.022 g, 0.047 mmol) was diluted withDCM (Volume: 2.0 ml) then charged with CDI (28 mg, 0.173 mmol). Thereaction mixture was then heated to 45° C. until complete consumption ofstarting acid was noted by LC/MS. At this time, cyclopropanesulfonamide(22.86 mg, 0.189 mmol) and DBU (7.11 μl, 0.047 mmol) were added and thereaction was heated for an additional 30 minutes. At this time, thereaction was quenched with 1N HCl, then diluted with DCM. The layerswere separated and the aqueous portion was extracted an addition twotimes with DCM. The organic portions were combined, dried (Na₂SO₄),filtered, and concentrated. The crude material was purified using SiO₂chromatography employing a 0-10% MeOH/DCM gradient to deliver thedesired acyl sulfonamide, Compound I-144 (16 mg, 54% yield).

¹H-NMR (400 MHz, CDCl₃) δ 10.62 (bs, 1H), 8.43 (d, 1H), 8.23 (d, 1H),7.45 (s, 1H), 7.19 (dd, 1H), 7.03-6.95 (m, 2H), 6.85 (t, 1H), 6.69 (s,1H), 5.96 (dd, 2H), 4.20-4.12 (m, 1H), 2.87-2.79 (m, 1H), 2.30-2.24 (m,1H), 2.02-1.92 (m, 1H), 1.86-1.70 (m, 4H), 1.30-0.86 (m, 6H).

Compound I-157

The title compound was prepared using the same procedure described forCompound I-144, with the exception of using Compound I-88 as thestarting carboxylic acid. Purification via silica gel chromatographydelivered the desired compound, Compound I-157 (10 mg, 55% yield) as asolid.

¹H-NMR (400 MHz, CD₃OD) δ 8.76 (d, 1H), 8.18 (d, 1H), 7.55 (s, 1H), 7.25(dd, 1H), 7.07 (t, 1H), 7.00 (t, 1H), 6.92 (d, 1H), 6.81 (t, 1H), 5.96(dd, 2H), 4.66-4.62 (m, 1H), 2.88-2.83 (m, 1H), 1.93-1.83 (m, 2H),1.31-1.27 (m, 2H), 1.16-1.10 (m, 1H), 1.04 (d, 3H), 0.97 (d, 3H),0.92-0.78 (m, 2H).

Compound I-187

The title compound was prepared using the same procedure described forCompound I-144, with the exception of using Compound I-89 as thestarting carboxylic acid. Purification via silica gel chromatographydelivered the desired compound, Compound I-187 (33 mg, 80% yield) as asolid.

¹H-NMR (400 MHz, DMSO-d₆) δ 11.92 (s, 1H), 9.09 (d, 1H), 8.33 (d, 1H),7.55 (s, 1H), 7.29 (dd, 1H), 7.18 (t, 1H), 7.12 (d, 1H), 7.07 (t, 1H),6.84 (t, 1H), 5.87 (s, 2H), 4.50 (d, 1H), 3.19 (d, 3H), 2.95-2.87 (m,1H), 2.42-2.35 (m, 1H), 1.05 (d, 3H), 1.02-0.94 (m, 2H), 0.89 (d, 3H),0.87-0.83 (m, 2H).

Compound I-272

The title compound was prepared following general procedure B, except(S)-3-methyl-2-(methylamino)butanoic acid was the amine reactant,3-(3-(4-chloropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole(synthesis described in procedure towards Compound I-24) was used inplace of Intermediate 1, and the contents were heated to 110° C. for 72h. The crude material was purified via silica gel chromatographyutilizing a 0-10% methanol/dichloromethane gradient to deliver thedesired compound, Compound I-272 (4 mg, 8% yield) as a solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 12.98 (bs, 1H), 9.07 (s, 1H), 8.24 (bs, 2H),7.48 (bs, 1H), 7.30 (dd, 1H), 7.19 (t, 1H), 7.07 (t, 1H), 6.84 (bs, 1H),6.60 (bs, 1H), 5.86 (s, 2H), 5.24 (bs, 1H), 2.94 (bs, 3H), 2.30 (bs,1H), 1.02 (d, 3H), 0.77 (d, 3H).

Compound I-74

Intermediate 1 was dissolved in THF and cooled to 0° C. In a separatevial, 1H-pyrazole (1 equiv.) was diluted with THF then charged withsodium hydride (60% in dispersion oil, 1 equiv.) to generate the sodiumsalt. The contents were allowed to stir for 15 min. At this time, thesodium salt was added portion-wise to the solution of Intermediate 1.Once starting material was consumed as observed on the LC/MS, thereaction was quenched with aqueous 1N HCl and the mixture was extractedwith dichloromethane (three times). The organic portions were combineddried, filtered, and concentrated. The crude material was then purifiedusing a 0-10% methanol/dichloromethane gradient to deliver the desiredcompound, Compound I-74 (41 mg, 72% yield).

¹H-NMR (400 MHz, DMSO-d₆) δ 9.10 (t, 1H), 9.03 (dd, 1H), 8.80-8.79 (m,1H), 8.02-8.00 (m, 1H), 7.81 (d, 1H), 7.34-7.28 (m, 1H), 7.24 (t, 1H),7.23-7.18 (m, 1H), 7.09 (t, 1H), 6.88 (t, 1H), 6.72-6.70 (m, 1H), 5.93(s, 2H).

Compound I-273

This compound was synthesized according to the general procedure B using2-((2,2,2-trifluoroethyl)amino)acetic acid hydrochloride. Followingcomplete consumption of starting material, the solution was diluted withaqueous 1N sodium hydroxide until pH˜10. Diethyl ether was added and thelayers were separated. The aqueous layer was acidified with aqueous 1Nhydrochloric acid until pH˜2. Ethyl acetate was added, and the layerswere again separated. The aqueous layer was extracted with ethyl acetateand the combined organics were dried over magnesium sulfate, filtered,and the solvent was removed under vacuum. Purification by silica gelchromatography (0-15% methanol in dichloromethane) provided compoundI-273 (6 mg, 23%) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.73 (m, 1H), 8.27 (d, 1H), 7.40 (s, 1H),7.27-7.22 (m, 1H), 7.09-6.99 (m, 2H), 6.87-6.86 (m, 1H), 6.80 (t, 1H),5.94 (s, 2H), 4.61-4.55 (m, 2H), 4.45 (s, 2H).

Compound I-274

The title compound was prepared following general procedure B, except3-((methylamino)methyl)benzoic acid (as the HCl salt) was the aminereactant, and contents were heated to 90° C. for 2 h as a solution indioxane. Ethyl acetate was used as the extraction solvent during workup.The crude compound Compound I-274 (20 mg, 68% yield) was isolated as awhite solid that did not require additional purification.

¹H-NMR (400 MHz, CD₃OD) δ 8.76 (m, 1H), 8.29 (d, 1H), 8.08 (s, 1H), 7.97(d, 1H), 7.65-7.63 (m, 1H), 7.54 (s, 1H), 7.48 (t, 1H), 7.30-7.24 (m,1H), 7.10-7.01 (m, 2H), 6.94-6.88 (m, 2H), 5.99 (s, 2H), 5.16 (s, 2H),3.48 (d, 3H).

Compound I-275

The title compound was prepared following general procedure B, except4-((methylamino)methyl)benzoic acid (as the HCl salt) was the aminereactant. Ethyl acetate was used as the extraction solvent duringworkup. The crude compound Compound I-275 (17 mg, 63% yield) wasisolated as a white solid that did not require additional purification.

¹H-NMR (400 MHz, DMSO-d₆) δ 12.88 (br s, 1H), 9.05 (m, 1H), 8.25 (d,1H), 7.87 (d, 2H), 7.48 (s, 1H), 7.44 (d, 2H), 7.32-7.27 (m, 1H),7.21-7.19 (m, 2H), 7.07 (t, 1H), 6.83 (t, 1H), 5.86 (s, 2H), 4.95 (s,2H), 3.24 (d, 3H).

Compound I-276

This compound was synthesized according to the general procedure B using1H-tetrazol-5-amine and dioxane as solvent. The crude residue wassuspended in dichloromethane and filtered. The filtrate was purified bysilica gel chromatography (0-10% methanol in dichloromethane) to providecompound I-276 (0.4 mg, 2% yield) as a white film.

¹H-NMR (400 MHz, CD₃OD) δ 8.75 (m, 1H), 8.42 (d, 1H), 7.48 (s, 1H),7.29-7.24 (m, 1H), 7.11-7.06 (m, 1H), 7.05-7.01 (m, 1H), 6.89-6.83 (m,2H), 5.97 (s, 2H).

Compound I-277

This compound was synthesized according to the general procedure B using3-amino-3-methylbutanoic acid and contents were heated to 80 C for 68 h.Purification by silica gel chromatography (0-10% methanol indichloromethane) provided compound I-277 (1.3 mg, 5% yield) as a whitefilm.

¹H-NMR (400 MHz, CD₃OD) δ 8.74 (m, 1H), 8.02 (d, 1H), 7.34 (d, 1H),7.27-7.22 (m, 1H), 7.09-7.00 (m, 2H), 6.89-6.83 (m, 2H), 5.93 (s, 2H),3.03 (s, 2H), 1.66 (s, 6H).

Compound I-278

This compound was synthesized according to the general procedure B using5-(aminomethyl)pyridin-2 (1H)-one and contents were stirred at 90° C.for 40 h. The crude reaction mixture was diluted with 1N aqueoushydrochloric acid and ethyl acetate. The layers were separated and theaqueous layer was concentrated under vacuum. Purification by reversephase HPLC (20-50% acetonitrile in water w/0.1% TFA, 20 min gradient)provided compound I-278 (13 mg, 35% yield) as a tan solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.82 (s, 1H), 8.28 (d, 1H), 7.73-7.64 (m, 3H),7.32-7.26 (m, 1H), 7.11-7.03 (m, 2H), 6.99-6.95 (m, 2H), 6.54 (d, 1H),6.01 (s, 2H), 4.73 (s, 2H).

Compound I-279

This compound was synthesized according to the general procedure B usingthe trifluoroacetic acid salt of 2-((methylamino)methyl)benzoic acidwith dioxane as solvent and contents were heated at 90° C. for 2 d.Purification of the crude reaction mixture by reverse phase HPLC (5-75%acetonitrile in water w/0.1% TFA, 20 min gradient) provided compoundI-279 (15 mg, 37% yield) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 13.17 (br s, 1H), 9.10 (m, 1H), 8.25 (d,1H), 7.94 (d, 1H), 7.56-7.52 (m, 1H), 7.44 (s, 1H), 7.41-7.29 (m, 3H),7.24-7.19 (m, 2H), 7.12-7.08 (m, 1H), 6.85-6.81 (m, 1H), 5.89 (s, 2H),5.24 (s, 2H), 3.30 (s, 3H).

Compound I-280

This compound was synthesized according to the general procedure B using4-(aminomethyl)benzoic acid with ethyl acetate as the extractionsolvent. Purification of the crude reaction mixture by reverse phaseHPLC (5-75% acetonitrile in water w/0.1% TFA, 20 min gradient) providedCompound I-280 (3.4 mg, 9% yield) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.81 (s, 1H), 8.26 (d, 1H), 8.02 (d, 2H), 7.58(d, 2H), 7.53 (s, 1H), 7.33-7.27 (m, 1H), 7.13-7.04 (m, 2H), 6.95-6.91(m, 2H), 6.01 (s, 2H), 5.01 (s, 2H).

Compound I-281

This compound was synthesized according to the general procedure B using6-methylpiperidine-2-carboxylic acid. Purification of the crude reactionmixture by silica gel chromatography (0-10% methanol in dichloromethane)provided Compound I-281 (3.4 mg, 9% yield) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.75 (d, 1H), 8.15 (d, 1H), 7.40 (s, 1H),7.29-7.23 (m, 1H), 7.11-7.06 (m, 1H), 7.02 (td, 1H), 6.88 (d, 1H),6.82-6.78 (m, 1H), 5.95 (s, 2H), 5.46 (br s, 1H), 2.46-2.43 (m, 1H),1.91-1.72 (m, 4H), 1.63-1.60 (m, 2H), 1.35 (d, 3H).

Compound I-282 and I-283

These were synthesized according to the general procedure B using amixture of (1R,4S)-4-methylpiperidine-2-carboxylic acid and(1S,4S)-4-methylpiperidine-2-carboxylic acid. Purification of the crudereaction mixture by silica gel chromatography (0-10% methanol indichloromethane) provided Compound I-282 (15 mg, 39% yield) as a whitesolid.

Repurification of the mixed fractions by reverse phase HPLC (5-75%acetonitrile in water w/0.1% TFA) provided Compound I-283 (4 mg, 10%yield).

Compound I-282: ¹H-NMR (400 MHz, CD₃OD) δ 8.74 (m, 1H), 8.22 (d, 1H),7.41 (s, 1H), 7.26-7.21 (m, 1H), 7.08-7.04 (m, 1H), 7.01-6.98 (m, 1H),6.84 (m, 1H), 6.81-6.78 (m, 1H), 5.93 (s, 2H), 4.44 (dd, 1H), 4.04-3.98(m, 1H), 3.65-3.60 (m, 1H), 2.19 (dt, 1H), 1.93-1.70 (m, 3H), 1.46-1.38(m, 1H), 1.04 (d, 3H).

Compound I-283: ¹H-NMR (400 MHz, CD₃OD) δ 8.77 (d, 1H), 8.28 (d, 1H),7.52 (s, 1H), 7.29-7.23 (m, 1H), 7.10-7.00 (m, 2H), 6.92 (d, 1H),6.88-6.85 (m, 1H), 5.97 (s, 2H), 5.68 (br s, 1H), 4.74 (br s, 1H), 3.41(br s, 1H), 2.44-2.39 (m, 1H), 1.87-1.82 (m, 1H), 1.74-1.65 (m, 1H),1.58-1.50 (m, 1H), 1.38-1.28 (dq, 1H), 1.00 (d, 3H).

Compound I-237

This compound was synthesized according to the general procedure B using(R)—N,2-dimethyl-1-(1H-tetrazol-5-yl)propan-1-amine (2 equivalents).Purification of the crude reaction mixture by reverse phase HPLC (5-75%acetonitrile in water w/0.1% TFA) provided Compound I-237 (4 mg, 23%yield) as a clear oil.

¹H-NMR (400 MHz, CD₃OD) δ 8.80 (m, 1H), 8.31 (d, 1H), 7.53 (s, 1H),7.28-7.25 (m, 1H), 7.09-7.01 (m, 3H), 6.96 (m, 1H), 6.05 (d, 1H), 5.98(d, 1H), 5.76 (br s, 1H), 3.35 (d, 3H), 2.86-2.80 (m, 1H), 1.07 (d, 3H),0.90 (d, 3H).

Compound I-284

This compound was synthesized according to the general procedure B using(R)-2-methyl-1-(1H-tetrazol-5-yl)propan-1-amine. Purification of thecrude reaction mixture by silica gel chromatography (0-10% methanol indichloromethane) provided Compound I-284 (16 mg, 37% yield) as a whitesolid.

¹H-NMR (400 MHz, CD₃OD) δ 8.75 (m, 1H), 8.12 (d, 1H), 7.27-7.21 (m, 2H),7.06-7.03 (m, 1H), 7.01-6.98 (m, 1H), 6.88 (d, 1H), 6.82-6.78 (m, 1H),5.96 (d, 1H), 5.91 (d, 1H), 5.50 (d, 1H), 2.61-2.52 (m, 1H), 1.14 (d,3H), 0.93 (d, 3H).

Compound I-285

To a solution of compound I-147 (previously described, 1 equivalent) andpyridine (50 equivalents) in dichloromethane at 0° C. was addedcyclopropanecarbonyl chloride (1.2 equivalents) over 30 seconds. Thesolution was immediately warmed to room temperature and stirred for anadditional 2.5 hours. After diluting with saturated aqueous ammoniumchloride and dichloromethane, the layers were separated and the aqueouslayer was extracted with dichloromethane. The organics were dried overmagnesium sulfate, filtered, and the solvent was removed under vacuum.Purification by silica gel chromatography (0-5% methanol indichloromethane) gave Compound I-285 (11 mg, 34% yield) as a whitesolid.

¹H-NMR (400 MHz, CD₃OD) δ 8.73 (m, 1H), 8.18 (d, 1H), 7.43 (s, 1H),7.27-7.22 (m, 1H), 7.09-7.04 (m, 1H), 7.00 (t, 1H), 6.90 (m, 1H), 6.77(t, 1H), 5.95 (s, 2H), 3.98-3.95 (m, 4H), 3.46-3.44 (m, 4H), 1.65-1.59(m, 1H), 0.92-0.84 (m, 4H).

Compound I-229

The title compound was prepared following general procedure B, except2-(piperidin-3-yl)acetic acid was the amine reactant, 6 equivalents ofHunig's base was used instead of triethylamine, and contents were heatedto 120° C. for 18 h as a solution in THF/water (10:1). Solvent wasremoved under a stream of nitrogen, and the resulting crude material waspurified via reverse phase HPLC to deliver the desired compound,Compound I-229 (8.1 mg, 32% yield) as a solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.84 (m, 1H), 8.28 (m, 1H), 7.73 (m, 1H),7.32 (m, 1H), 7.12 (m, 2H), 6.98 (m, 2H), 6.04 (s, 2H), 4.96 (m, 1H),4.67 (m, 1H), 3.54 (m, 1H), 3.27 (m, 1H), 2.42 (m, 2H), 2.25 (m, 1H),2.00 (m, 2H), 1.79 (m, 1H), 1.54 (m, 1H).

Compound I-230 and Compound I-231

The title compound was prepared following general procedure B, except amixture of 2-(piperidin-4-yl)acetic acid and methyl2-(piperidin-4-yl)acetate was the amine reactant, 6 equivalents ofHunig's base was used instead of triethylamine, and contents were heatedto 120° C. for 18 h as a solution in THF/water (10:1). Solvent wasremoved under a stream of nitrogen, and the resulting crude material waspurified via reverse phase HPLC to deliver the desired compounds,Compound I-230 (6.5 mg, 25% yield) as a solid, and Compound I-231 (16.2mg, 61% yield) as a solid.

¹H NMR for Compound I-230 (500 MHz, METHANOL-d₄) δ ppm 8.83 (m, 1H),8.26 (m, 1H), 7.63 (m, 1H), 7.30 (m, 1H), 7.10 (m, 2H), 6.97 (m, 2H),6.03 (s, 2H), 4.98 (m, 2H), 3.40 (m, 1H), 2.35 (m, 2H), 2.25 (m, 1H),2.04 (m, 2H), 1.50 (m, 2H).

¹H NMR for Compound I-231 (500 MHz, METHANOL-d₄) δ ppm 8.84 (m, 1H),8.30 (m, 1H), 7.66 (m, 1H), 7.28-7.37 (m, 1H), 7.05-7.17 (m, 2H), 7.00(d, 2H), 6.04 (s, 2H), 4.93-5.02 (m, 2H), 3.70 (s, 3H), 3.35-3.45 (m,2H), 2.358 (d, 2H), 2.22-2.34 (m, 1H), 1.99-2.08 (m, 2H), 1.50 (br.s.,2H).

Compound I-232

The title compound was prepared following general procedure B, except2-amino-4-methoxybutanoic acid was the amine reactant, 6 equivalents ofHunig's base was used instead of triethylamine, and contents were heatedto 120° C. for 18 h as a solution in THF/water (10:1). Solvent wasremoved under a stream of nitrogen, and the resulting crude material waspurified via reverse phase HPLC to deliver the desired compound,Compound I-232 (10 mg, 40% yield) as a solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.80 (m, 1H), 8.32 (m, 1H), 7.55 (s, 1H),7.29 (m, 1H), 7.08 (m, 2H), 6.96 (m, 2H), 6.01 (s, 2H), 5.11 (m, 1H),3.61 (m, 2H), 3.35 (s, 3H), 2.43 (m, 1H), 2.21 (m, 1H).

Compound I-234

The title compound was prepared following general procedure B, except3-(piperidin-4-yl)propanoic acid was the amine reactant. Solvent wasremoved under a stream of nitrogen, and the resulting crude material waspurified via reverse phase HPLC to deliver the desired compound,Compound I-234 (13 mg, 49% yield) as a solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.81-8.86 (m, 1H), 8.25-8.31 (m, 1H),7.61-7.67 (m, 1H), 7.29-7.36 (m, 1H), 7.05-7.16 (m, 2H), 6.95-7.02 (m,2H), 6.04 (s, 2H), 4.93-5.02 (m, 2H), 3.37 (s, 2H), 2.36-2.45 (m, 2H),1.96-2.06 (m, 2H), 1.76-1.88 (m, 1H), 1.61-1.70 (m, 2H), 1.35-1.48 (m,2H).

Compound I-286

The title compound was prepared following general procedure B, except4-(aminomethyl)phenol was the amine reactant (1.1 equiv.), 4 equivalentsof triethylamine was used, and contents were heated to 90° C. for 12 has a solution in dioxane/water (10:1). The crude material was purifiedvia silica gel chromatography utilizing a 1-5% methanol/dichloromethanegradient over 40 min to deliver the desired compound, Compound I-286(17.7 mg, 48% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.45 (d, 1H), 8.16 (d, 1H), 7.34 (s,1H), 7.16-7.24 (m, 3H), 6.99-7.04 (m, 1H), 6.94-6.99 (m, 1H), 6.85-6.90(m, 1H), 6.79-6.83 (m, 2H), 6.58 (d, 1H), 5.97 (s, 2H), 5.67 (br. s,1H), 5.28-5.30 (m, 1H), 4.72 (d, 2H).

Compound I-287

The title compound was prepared following general procedure B, except(4-(methylsulfonyl)phenyl)methanamine was the amine reactant (1 equiv.),4 equivalents of triethylamine was used, and contents were heated to 90°C. for 12 h as a solution in dioxane/water (10:1). The crude materialwas purified via silica gel chromatography utilizing a 1-5%methanol/dichloromethane gradient over 40 min to deliver the desiredcompound, Compound I-287 (23.3 mg, 56% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.47 (d, 1H), 8.22 (m, 1H), 7.90-7.96(m, 2H), 7.64-7.68 (m, 2H), 7.20-7.25 (m, 2H), 6.98-7.08 (m, 2H),6.88-6.93 (m, 1H), 6.57 (d, 1H), 5.98 (s, 2H), 5.52-5.63 (br. d, 1H),4.93-4.97 (m, 2H), 3.06 (s, 3H).

Compound I-288

The title compound was prepared following general procedure B, except2-(aminomethyl)phenol was the amine reactant (1.1 equiv.), 4 equivalentsof triethylamine was used, and contents were heated to 90° C. for 12 has a solution in dioxane/water (10:1). The crude material was purifiedvia silica gel chromatography utilizing a 1-5% methanol/dichloromethanegradient over 40 min to deliver the desired compound, Compound I-288(4.5 mg, 12% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 9.52 (s, 1H), 8.49 (d, 1H), 8.15 (d,1H), 7.42 (s, 1H), 7.21-7.27 (m, 3H), 7.02-7.11 (m, 3H), 6.89-6.95 (m,2H), 6.64 (d, 1H), 6.03 (s, 2H), 5.80-5.85 (m, 1H), 4.75 (d, 2H).

Compound I-289

The title compound was prepared following general procedure B, except2-(4-methylpiperidin-4-yl)acetic acid (as the HCl salt, 1.15 equiv.) wasthe amine reactant, 4 equivalents of triethylamine was used, andcontents were heated to 90° C. for 12 h as a solution in dioxane/water(3:1). A dichloromethane/isopropanol mix (5:1) was used as theextraction solvent. The crude material was purified via silica gelchromatography utilizing a 1-5% methanol/dichloromethane gradient over40 min to deliver the desired compound, Compound I-289 (37.4 mg, 70%yield) as a foamy white solid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.45 (s, 1H), 8.12 (d, 1H), 7.30 (s,1H), 7.16-7.22 (m, 1H), 7.00-7.06 (m, 1H), 6.94-6.98 (m, 1H), 6.82-6.88(m, 1H), 6.59 (d, 1H), 5.97 (s, 2H), 3.83-3.96 (m, 2H), 3.59 (s, 2H),2.42-2.49 (m, 2H), 1.76-1.86 (m, 4H), 1.15 (s, 3H).

Compound I-290

The title compound was prepared following general procedure B, except4-cyclohexylpiperidine-4-carboxylic acid (as the TFA salt, 1.2 equiv.)was the amine reactant, 4 equivalents of triethylamine was used, andcontents were heated to 90° C. for 12 h as a solution in dioxane/water(3:1). A dichloromethane/isopropanol mix (5:1) was used as theextraction solvent. The crude material was purified via silica gelchromatography utilizing a 1-5% methanol/dichloromethane gradient over40 min to deliver the desired compound, Compound I-290 (44.6 mg, 76%yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.47 (s, 1H), 8.17 (d, 1H), 7.31 (s,1H), 7.16-7.24 (m, 1H), 7.01-7.08 (m, 1H), 6.95-7.00 (m, 1H), 6.83-6.88(m, 1H), 6.60 (d, 1H), 5.99 (s, 2H), 4.58-4.65 (m, 2H), 3.07-3.18 (m,2H), 2.24-2.32 (m, 2H), 1.77-1.86 (m, 4H), 1.45-1.70 (m, 3H), 1.13-1.26(m, 3H), 1.03-1.13 (m, 3H).

Compound I-291

The title compound was prepared following general procedure B, exceptmethyl 2-phenylpiperidine-2-carboxylate was the amine reactant, 4equivalents of sodium biocarbonate instead of triethylamine was used,and contents were heated to 110° C. for 48 h. Ethyl acetate was used asthe extraction solvent. First pass purification was achieved by silicagel chromatography using 1 to 5% methanol in dichloromethane gradientover 40 minutes to afford the product with 80% purity. Furtherpurification was achieved using by reverse phase HPLC using a 5 to 95%acetonitrile in water gradient over 30 minutes to deliver theanalytically pure desired compound, Compound I-291 (2 mg, 3% yield) as awhite solid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.41 (s, 1H), 8.35 (br. s, 1H),7.24-7.27 (m, 2H), 7.09-7.18 (m, 3H), 7.02-7.09 (m, 1H), 6.90-7.00 (m,2H), 6.79-6.87 (m, 1H), 6.67-6.74 (m, 1H), 6.44-6.51 (m, 1H), 5.86 (d,1H), 5.74 (d, 1H), 3.72-3.85 (m, 1H), 3.36-3.51 (m, 1H), 2.47-2.56 (m,1H), 1.70-1.99 (m, 5H).

Compound I-292

The title compound was prepared following general procedure B, except4-amino-2-phenylbutanoic acid (as the HCl salt) was the amine reactant,4 equivalents of triethylamine was used, and contents were heated to 95°C. for 12 h. Ethyl acetate was used as the extraction solvent. The crudematerial was purified via silica gel chromatography using a 1 to 5%methanol in dichloromethane gradient over 40 minutes to deliver thedesired compound, Compound I-292 (37.9 mg, 50% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.47 (d, 1H), 8.13 (d, 1H), 7.29-7.36(m, 6H), 7.15-7.23 (m, 1H), 6.99-7.04 (m, 1H), 6.92-6.97 (m, 1H),6.86-6.91 (m, 1H), 6.60 (d, 1H), 6.01 (d, 1H), 5.94 (d, 1H), 5.21-5.28(m, 1H), 3.85-3.94 (m, 1H), 3.62-3.80 (m, 2H), 2.51-2.61 (m, 1H),2.11-2.19 (m, 1H).

Compound I-293

The title compound was prepared following general procedure B, except4-methoxypiperidine-4-carboxylic acid (as the TFA salt) was the aminereactant (2 equiv.), 4 equivalents of triethylamine was used, andcontents were heated to 105° C. as a solution in dioxane/water (3:1) for12 h. Ethyl acetate was used as the extraction solvent. The crudematerial was purified via silica gel chromatography using a 1 to 5%methanol in dichloromethane gradient over 40 minutes to deliver thedesired compound, Compound I-293 (52.7 mg, 56% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.47 (s, 1H), 8.22 (d, 1H), 7.31 (s,1H), 7.16-7.25 (m, 1H), 7.01-7.09 (m, 1H), 6.95-7.01 (m, 1H), 6.84-6.89(m, 1H), 6.60 (d, 1H), 5.98 (s, 2H), 4.33-4.41 (m, 2H), 3.53-3.62 (m,2H), 3.41 (s, 3H), 2.05-2.20 (m, 4H).

Compound I-294

The title compound was prepared following general procedure B, except2-(piperidin-4-yl)propanoic acid was the amine reactant (2 equiv.), 4equivalents of triethylamine was used, and contents were heated to 90°C. for 12 h as a solution in dioxane/water (3:1). Adichloromethane/isopropanol mix (5:1) was used as the extractionsolvent. The crude material was purified via silica gel chromatographyusing a 1 to 5% methanol in dichloromethane gradient over 40 minutes todeliver the desired compound, Compound I-294 (42.8 mg, 68% yield) as anoff-white solid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.47 (s, 1H), 8.20 (d, 1H), 7.31 (s,1H), 7.17-7.23 (m, 1H), 7.00-7.07 (m, 1H), 6.94-7.02 (m, 1H), 6.81-6.89(m, 1H), 6.60 (d, 1H), 5.98 (s, 2H), 4.70-4.84 (m, 2H), 3.01-3.06 (t,2H), 2.39-2.44 (m, 1H), 1.93-2.01 (m, 1H), 1.82-1.93 (m, 2H), 1.37-1.54(m, 2H), 1.24 (d, 3H).

Compound I-295

The title compound was prepared following general procedure B, except4-phenylpiperidine-2-carboxylic acid (as the TFA salt) was the aminereactant (2 equiv.), 4 equivalents of triethylamine was used, andcontents were heated to 110° C. for 64 h. Ethyl acetate was used as theextraction solvent. The crude material was purified via silica gelchromatography using a 1 to 5% methanol in dichloromethane gradient over40 minutes to deliver the desired compound, Compound I-295 (12.0 mg, 18%yield) as a racemic mixture with a relative cis configuration (anoff-white solid).

¹H NMR (500 MHz, CD₃OD) δ (ppm): 8.76 (s, 1H), 8.21 (d, 1H), 7.45 (s,1H), 7.25-7.36 (m, 5H), 7.19-7.25 (m, 1H), 7.08-7.14 (m, 1H), 7.02-7.07(m, 1H), 6.91 (d, 1H), 6.80-6.86 (m, 1H), 5.97 (s, 2H), 5.62-5.77 (m,1H), 2.77-2.89 (m, 1H), 2.55-2.62 (m, 1H), 2.03-2.12 (m, 1H), 1.96-2.02(m, 1H), 1.83-1.96 (m, 1H), 1.25-1.35 (m, 1H), 0.84-0.98 (m, 1H).

Compound I-296

The title compound was prepared following general procedure B, except4-(4-methoxyphenyl)piperidine-4-carboxylic acid (as the TFA salt) wasthe amine reactant (2 equiv.), 4 equivalents of triethylamine was used,and contents were heated to 110° C. for 17 h as a solution indioxane/water (3:1). Ethyl acetate was used as the extraction solvent.The crude material was purified via silica gel chromatography using a 1to 5% methanol in dichloromethane gradient over 40 minutes to deliverthe desired compound, Compound I-296 (41.1 mg, 66% yield) as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.43 (s, 1H), 8.12 (d, 1H), 7.34 (d,2H), 7.28 (s, 1H), 7.12-7.16 (m, 1H), 6.94-7.02 (m, 1H), 6.88-6.93 (m,1H), 6.86 (d, 2H), 6.75-6.80 (m, 1H), 6.56 (d, 1H), 5.94 (s, 2H),4.44-4.52 (m, 2H), 3.78 (s, 3H), 3.36-3.41 (m, 2H), 2.63-2.72 (m, 2H),1.96-2.08 (m, 2H).

Compound I-298

The title compound was prepared following general procedure B, except4-aminopiperidine-4-carboxylic acid (as the HCl salt) was the aminereactant (2 equiv.), and contents were heated to 100° C. for 18 h as asolution in THF/DMF/triethylamine (1:1:1). After complete consumption ofthe starting material, the reaction was cooled to 0° C. and an excess of2M solution of trimethylsilyldiazomethane was added and stirred at 23°C. for 3 d until complete conversion to the amino ester. Contents werediluted with 1N NaOH solution, and extracted with dichloromethane. Theorganic layer was dried, filtered, and concentrated in vacuo. The crudematerial was purified via silica gel chromatography using a 20 to 100%ethyl acetate in hexanes gradient to deliver the desired compound,Compound I-298 (22 mg, 63% yield) as a solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.08 (d, 1H), 8.28 (d, 1H), 7.54 (s,1H), 7.29-7.39 (m, 1H), 7.18-7.27 (m, 2H), 7.10 (t, 1H), 6.83 (t, 1H),5.90 (s, 2H), 4.02-4.09 (m, 2H), 3.66-3.74 (m, 2H), 3.63-3.65 (m, 3H),1.99-2.04 (m, 2H), 1.91-1.98 (m 2H), 1.62 (d, 2H).

Compound I-299

The title compound was prepared following general procedure B, except4-aminopiperidine-4-carboxylic acid (as the HCl salt) was the aminereactant (5 equiv.), 8 equivalents of triethylamine was used, andcontents were heated to 90° C. for 18 h as a solution in THF/water(5:1). After complete consumption of the starting material, the reactionwas cooled and filtered. The resulting solids were collected andpurified via reverse phase HPLC to deliver the desired compound,Compound I-299 (2 mg, 7% yield) as a solid.

¹H NMR (500 MHz, METHANOL-d₄) δ ppm 8.80 (d, 1H), 8.31 (d, 1H), 7.54 (s,1H), 7.23-7.35 (m, 1H), 7.08-7.15 (m, 1H), 7.05 (t, 1H), 6.92 (d, 1H),6.81-6.90 (m, 1H), 5.99 (s, 2H), 4.45 (dt, 2H), 3.96-4.13 (m, 2H), 2.44(dt, 2H), 2.02 (ddd, 2H).

Compound I-300

The title compound was prepared following general procedure B, except4-hydroxypiperidine-4-carboxylic acid (as the HCl salt) was the aminereactant (5 equiv.), 8 equivalents of triethylamine was used, andcontents were heated to 90° C. as a solution in THF/water (5:1) for 18h. After complete consumption of the starting material, the reaction wascooled and filtered. The filtrated was collected and concentrated invacuo. The crude material was purified via reverse phase HPLC to deliverthe desired compound, Compound I-300 (22 mg, 81% yield) as a solid.

¹H NMR (500 MHz, METHANOL-d₄) δ ppm 8.83 (d, 1H), 8.22-8.35 (m, 1H),7.58-7.70 (m, 1H), 7.25-7.37 (m, 1H), 7.04-7.18 (m, 2H), 6.90-7.02 (m,2H), 6.03 (s, 2H), 4.76 (d, 2H), 3.69-3.82 (m, 2H), 2.16-2.33 (m, 2H),1.94 (d, 2H).

Compound I-301

The title compound was prepared following general procedure B, except(S)-4,4-difluoropyrrolidine-2-carboxylic acid was the amine reactant (5equiv.), 8 equivalents of triethylamine was used, and contents wereheated to 90° C. for 18 h as a solution in THF/water (5:1). Aftercomplete consumption of the starting material, the reaction wasconcentrated in vacuo. The crude material was purified via reverse phaseHPLC to deliver the desired compound, Compound I-301 (20 mg, 67% yield)as a solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.80 (d, 1H), 8.34 (d, 1H), 7.35-7.42 (m,1H), 7.24-7.34 (m, 1H), 7.10 (dd, 1H), 7.01-7.07 (m, 1H), 6.91 (td, 2H),5.98 (s, 2H), 5.44-5.69 (m, 2H) 4.76-4.87 (m, 3H).

Compound I-302

The title compound was prepared following general procedure B, except(S)-2-amino-3-ethoxypropanoic acid was the amine reactant (4 equiv.), 6equivalents of triethylamine was used, and contents were heated to 100°C. for 18 h as a solution in dioxane/water (3:1). After workup, thecrude material was suspended in ethyl acetate and diluted with hexanesuntil precipitation occurred. The precipitate was filtered and collectedto deliver the desired compound, Compound I-302 (9 mg, 24% yield) as asolid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.08 (s, 1H), 8.20 (d, 1H), 7.47 (s,1H), 7.27-7.40 (m, 2H), 7.17-7.26 (m, 2H), 7.10 (t, 1H), 6.84 (t, 1H),5.81-5.98 (m, 2H), 4.59 (br. s., 1H), 3.83-3.90 (m, 1H), 3.75-3.83 (m,1H), 3.45-3.54 (m, 1H), 3.37-3.44 (m, 1H), 0.92-1.08 (m, 3H).

Compound I-303

The title compound was prepared following general procedure B, except2-amino-3-methoxypropanoic acid was the amine reactant (4 equiv.), 6equivalents of triethylamine was used, and contents were heated to 100°C. for 18 h as a solution in dioxane/water (3:1). After workup, thecrude material was suspended in ethyl acetate and diluted with hexanesuntil precipitation occurred. The precipitate was filtered and collectedto deliver the desired compound, Compound I-303 (8 mg, 22% yield) as asolid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.09 (d, 1H) 8.22 (d, 1H), 7.47 (s, 1H),7.28-7.39 (m, 1H), 7.17-7.27 (m, 2H), 7.10 (t, 1H), 6.85 (t, 1H), 6.63(br. s., 1H), 5.81-5.94 (m, 2H), 4.54-4.88 (m, 1H), 3.72-3.87 (m, 2H),3.57 (s, 2H), 3.25 (s, 3H).

Compound I-304

The title compound was prepared following step 3 of the proceduredescribed for Compound I-235, except1-((methylamino)methyl)cyclopropanecarboxylic acid (as the TFA salt) wasthe amine reactant, and contents were heated to 100° C. for 6 h. Thecrude material was purified via silica gel chromatography (1-4% methanolin dichloromethane gradient) to deliver the desired compound, CompoundI-304 (67 mg, 72% yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.77 (d, 1H), 8.10 (d, 1H), 7.39 (s, 1H), 7.16(app. q, 1H), 7.03 (app. q, 1H), 6.92 (d, 1H), 6.68 (app. t, 1H), 5.98(s, 2H), 4.15 (s, 2H), 3.37 (d, 3H), 1.28 (m, 2H), 1.07 (m, 2H).

Compound I-305

The title compound was prepared following step 3 of the proceduredescribed for Compound I-235, except(2R,3S)-3-methylpiperidine-2-carboxylic acid (as the acetic acid salt)was the amine reactant, and contents were heated to 100° C. for 21 h.The crude material was purified via silica gel chromatography (2-4%methanol in dichloromethane gradient) to deliver the desired compound,Compound I-305 (24 mg, 46% yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.77 (d, 1H), 8.21 (d, 1H), 7.47 (s, 1H), 7.15(app. q, 1H), 7.02 (app. q, 1H), 6.89 (d, 1H), 6.66 (app. t, 1H), 5.98(s, 2H), 5.04 (d, 1H), 4.37 (br. d, 1H), 3.70 (app. t, 1H), 2.10 (m,1H), 1.90 (br. d, 1H), 1.80-1.69 (m, 2H), 1.52 (app. q, 1H), 1.21 (d,3H).

Compound I-306

The title compound was prepared following general procedure B, except4-isopropylpiperidine-4-carboxylic acid was the amine reactant, and thecontents were heated to 90° C. for 3 h as a solution in THF/water(10:1). The contents were cooled to 23° C., and organic solvents wereremoved in vacuo. Solids were treated with 1N HCl solution, and theresulting precipitate was filtered and dried in vacuo to deliver thedesired compound, Compound I-306 (42 mg, 86% yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.49 (d, 1H), 8.35 (d, 1H), 7.64 (s, 1H),7.25-7.20 (m, 1H), 7.05-7.01 (m, 3H), 6.67 (d, 1H), 5.98 (s, 2H), 4.80(d, 2H), 3.79-3.72 (m, 1H), 3.23 (t, 1H), 2.35 (d, 2H), 1.92-1.80 (m,1H), 1.62 (td, 1H), 1.41 (t, 1H), 0.97 (d, 6H).

Compound I-307

The title compound was prepared following general procedure B, except3-(methylamino)bicyclo[1.1.1]pentane-1-carboxylic acid was the aminereactant, and the contents were heated to 90° C. for 18 h as a solutionin THF/water (10:1). The crude material was purified via silica gelchromatography utilizing a 0-10% methanol/dichloromethane gradient todeliver the desired compound, Compound I-307 (74 mg, 53% yield) as anoff-white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.53 (d, 1H), 8.45 (d, 1H), 7.49 (s, 1H),7.26-7.21 (m, 2H), 7.09-7.01 (m, 2H), 6.67 (d, 1H), 5.93 (s, 2H), 3.36(d, 3H), 2.68 (s, 6H).

Compound I-308

The title compound was prepared following general procedure B, except2-azabicyclo[4.1.0]heptane-1-carboxylic acid (as the HCl salt) was theamine reactant, and the contents were heated to 90° C. for 3 h as asolution in THF/water (10:1). The crude material was purified via silicagel chromatography utilizing a 0-10% methanol/dichloromethane gradientto deliver the desired compound, Compound I-308 (32 mg, 17% yield) as anoff-white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.46 (d, 1H), 8.21 (d, 1H), 7.27 (s, 1H),7.23-7.18 (m, 1H), 7.04 (t, 1H), 6.98 (t, 1H), 6.87 (t, 1H), 6.59 (d,1H), 5.98 (s, 2H), 4.62 (br. s., 1H), 3.01 (br. s., 1H), 2.20-2.11 (m,1H), 2.08-1.98 (m, 2H), 1.83-1.72 (m, 2H), 1.57-1.49 (m, 1H), 1.04 (br.s., 1H).

Compound I-309

The title compound was prepared following general procedure B, except(1R,3S)-3-(Boc-amino)cyclopentane-1-carboxylic acid (as the TFA salt)was the amine reactant, and the contents were heated to 90° C. for 3 has a solution in THF/water (10:1). The crude material was purified viasilica gel chromatography utilizing a 0-10% methanol/dichloromethanegradient to deliver an intermediate. This intermediate was immediatelydissolved in THF, and cooled to 0° C. Contents treated with sodiumhydride (60% in mineral oil, 2 equiv.) followed by methyl iodide (10equiv.). Reaction was allowed to warm to 23° C. over 3 d. Contentspoured over water, and extracted with ethyl acetate (3×). The organicportions were combined and washed with brine. The mixture was dried overMgSO₄, filtered, and concentrated in vacuo. The crude material waspurified via silica gel chromatography utilizing a 0-15%methanol/dichloromethane gradient to deliver the desired compound,Compound I-309 (0.9 mg, 1% yield) as an off-white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.45 (s, 1H), 8.13 (d, 1H), 7.32 (s, 1H),7.23-7.15 (m, 1H), 7.03 (t, 1H), 6.97 (t, 1H), 6.86 (t, 1H), 6.60 (s,1H), 5.97 (s, 2H), 4.75 (d, 1H), 3.74 (s, 3H), 3.08-2.94 (m, 1H),2.42-2.30 (m, 1H), 2.17-1.84 (m, 5H).

Compound I-310

The title compound was prepared following general procedure B, except(2S, 3S)-2-Methyl-piperidine-3-carboxylic acid was the amine reactant,and the contents were heated to 90° C. as a solution in THF/water (10:1)for 3 d. The crude material was purified via silica gel chromatographyutilizing a 0-50% (acetonitrile:methanol=9:1 with 0.1%TFA)/dichloromethane gradient to deliver the desired compound, CompoundI-310 (4.9 mg, 2% yield) as an off-white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.46 (d, 1H), 8.22 (d, 1H), 7.31 (s, 1H),7.24-7.18 (m, 1H), 7.13-7.01 (m, 1H), 6.98 (t, 1H), 6.87 (t, 1H), 6.59(d, 1H), 5.97 (s, 2H), 5.38 (br. s., 1H), 4.42 (d, 1H), 3.22 (t, 1H),2.99-2.87 (m, 1H), 2.05-1.96 (m, 2H), 1.93-1.84 (m, 2H), 1.32 (d, 3H).

Compound I-311

The title compound was prepared following general procedure B, except(2R, 3R)-2-Methyl-piperidine-3-carboxylic acid was the amine reactant,and the contents were heated to 90° C. for 18 h as a solution inTHF/water (10:1). The crude material was purified via silica gelchromatography utilizing a 0-10% methanol/dichloromethane gradient todeliver the desired compound, Compound I-311 (17.2 mg, 12% yield) as anoff-white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ 12.51 (br. s., 1H), 9.09 (d, 1H), 8.31 (d,1H), 7.50 (s, 1H), 7.36-7.29 (m, 1H), 7.25-7.18 (m, 2H), 7.10 (t, 1H),6.84 (t, 1H), 5.89 (s, 2H), 5.09 (br. s., 1H), 4.37 (br. s., 1H), 3.10(t, 1H), 2.74 (br. s., 1H), 1.84-1.72 (m, 3H), 1.50 (br. s., 1H), 1.19(d, 3H).

Compound I-312

The title compound was prepared following general procedure B, except3-azabicyclo[3.1.0]hexane-1-carboxylic acid (as the HCl salt) was theamine reactant, the contents were heated to 100° C. for 18 h, and theaqueous layer during workup was treated with sodium chloride. The crudematerial was purified via silica gel chromatography utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-312 (44 mg, 70% yield) as an off-white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ 12.65 (br. s., 1H), 9.08 (d, 1H), 8.26 (d,1H), 7.53 (s, 1H), 7.35-7.30 (m, 1H), 7.26 (d, 1H), 7.25-7.20 (m, 1H),7.10 (td, 1H), 6.83-6.79 (m, 1H), 5.91 (s, 2H), 4.09-3.98 (m, 3H), 3.81(br. s., 1H), 2.22-2.17 (m, 1H), 1.51 (dd, 1H), 0.97 (t, 1H).

Compound I-313

The title compound was prepared following general procedure B, except(S)-3-aminopropane-1,2-diol was the amine reactant, the contents wereheated to 100° C. for 20 h, and the aqueous layer during workup wastreated with sodium chloride. The crude material was purified via silicagel chromatography utilizing a 0-10% methanol/dichloromethane gradientto deliver the desired compound, Compound I-313 (39 mg, 85% yield) as anoff-white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.74 (d, 1H), 8.07 (d, 1H), 7.42 (s, 1H),7.29-7.22 (m, 1H), 7.11-7.05 (m, 1H), 7.02 (td, 1H), 6.88 (d, 1H), 6.81(td, 1H), 5.95 (s, 2H), 3.88 (quin, 1H), 3.81-3.74 (m, 1H), 3.69-3.62(m, 1H), 3.59 (s, 1H), 3.58 (s, 1H).

Compound I-314

The title compound was prepared following general procedure B, exceptcis-4-methylpyrrolidine-3-carboxylic acid was the amine reactant, thecontents were heated to 100° C. for 20 h, and the aqueous layer duringworkup was treated with sodium chloride. The crude material was purifiedvia silica gel chromatography utilizing a 0-10% methanol/dichloromethanegradient to deliver the desired compound, Compound I-314 (50 mg, 72%yield) as an off-white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.74 (d, 1H), 8.09 (d, 1H), 7.41 (s, 1H),7.29-7.23 (m, 1H), 7.11-7.06 (m, 1H), 7.02 (t, 1H), 6.91 (d, 1H), 6.81(t, 1H), 5.95 (s, 2H), 4.22-4.13 (m, 2H), 3.98-3.92 (m, 1H), 3.41 (t,1H), 2.84-2.77 (m, 1H), 2.58 (d, 1H), 1.24 (d, 3H).

Compound I-315

The title compound was prepared following general procedure B, exceptserinol was the amine reactant, the contents were heated to 100° C. for20 h, and the aqueous layer during workup was treated with sodiumchloride. The crude material was purified via silica gel chromatographyutilizing a 0-10% methanol/dichloromethane gradient to deliver thedesired compound, Compound I-315 (49 mg, 84% yield) as an off-whitesolid.

¹H-NMR (500 MHz, CD₃OD) δ 8.75 (t, 1H), 8.08 (dd, 1H), 7.46 (d, 1H),7.30-7.23 (m, 1H), 7.09 (dd, 1H), 7.03 (t, 1H), 6.91-6.88 (m, 1H), 6.80(t, 1H), 5.96 (s, 2H), 4.54 (quin, 1H), 3.75-3.82 (m, 4H).

Compound I-316

The title compound was prepared following general procedure B, except(R)-3-aminopropane-1,2-diol (2 equiv.) was the amine reactant, thecontents were heated to 100° C. for 20 h, and the aqueous layer duringworkup was treated with sodium chloride. The crude material was purifiedvia silica gel chromatography utilizing a 0-10% methanol/dichloromethanegradient to deliver the desired compound, Compound I-316 (36 mg, 78%yield) as an off-white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.73 (d, 1H), 8.06 (d, 1H), 7.41 (s, 1H),7.27-7.22 (m, 1H), 7.10-7.04 (m, 1H), 7.01 (t, 1H), 6.86 (d, 1H),6.83-6.78 (m, 1H), 5.94 (s, 2H), 3.88 (quin, 1H), 3.80-3.74 (m, 1H),3.68-3.62 (m, 1H), 3.58 (d, 2H).

Compound I-317

The title compound was prepared following general procedure B, except4-(aminomethyl)-2,6-difluorophenol was the amine reactant, the contentswere heated to 100° C. for 20 h, and the aqueous layer during workup wastreated with sodium chloride. The crude material was purified via silicagel chromatography utilizing a 0-30%(acetonitrile:methanol=7:1)/dichloromethane gradient to deliver thedesired compound, Compound I-317 (38 mg, 30% yield) as an off-whitesolid.

¹H-NMR (500 MHz, CD₃OD) δ 8.77-8.74 (m, 1H), 8.08 (d, 1H), 7.37 (s, 1H),7.26 (dd, 1H), 7.11-7.06 (m, 1H), 7.06-7.01 (m, 3H), 6.88 (d, 1H), 6.84(t, 1H), 5.96 (s, 2H), 4.69 (s, 2H).

Compound I-318

The title compound was prepared following general procedure B, exceptcis-piperidine-2,4-diyldimethanol was the amine reactant and thecontents were heated to 100° C. for 20 h. The reaction was poured into a1:1 mix of dichloromethane and water for workup, and the aqueous layerwas treated with sodium chloride before extraction with dichloromethane.The crude material was purified via silica gel chromatography utilizinga 0-70% (acetonitrile:methanol=7:1)/dichloromethane gradient to deliverthe desired compound, Compound I-318 (39 mg, 25% yield) as an off-whitesolid.

¹H-NMR (500 MHz, CD₃OD) δ 8.75 (d, 1H), 8.12 (d, 1H), 7.40 (s, 1H),7.29-7.23 (m, 1H), 7.11-7.05 (m, 1H), 7.04-6.99 (m, 1H), 6.90 (d, 1H),6.82 (td, 1H), 5.99-5.91 (m, 2H), 4.52-4.45 (m, 1H), 4.35-4.26 (m, 1H),3.86-3.76 (m, 2H), 3.58-3.42 (m, 3H), 2.09-1.99 (m, 2H), 1.85-1.75 (m,1H), 1.65-1.55 (m, 1H), 1.45-1.36 (m, 1H).

Compound I-319

The title compound was prepared following general procedure B, except3-phenylpiperidine-2-carboxylic acid (as the AcOH salt) was the aminereactant, the contents were heated to 100° C. for 20 h, and the aqueouslayer during workup was treated with sodium chloride. A portion of thecrude material was purified via reverse phase HPLC utilizing a 5-75%acetonitrile/water gradient to deliver the desired compound, CompoundI-319 (30 mg, 9% yield) as an off-white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.37 (d, 1H), 8.27 (d, 1H), 7.34-7.28 (m, 4H),7.26-7.22 (m, 1H), 7.20 (s, 1H), 7.15 (ddd, 1H), 6.99-6.88 (m, 3H), 6.45(d, 1H), 5.91-5.82 (m, 2H), 5.18 (d, 1H), 4.31 (d, 1H), 3.59 (td, 1H),3.26-3.17 (m, 1H), 2.49 (qd, 1H), 2.06-1.99 (m, 1H), 1.98-1.81 (m, 2H).

Compound I-320

The title compound was prepared following general procedure B, except(S)-3-(methylamino)propane-1,2-diol was the amine reactant and thecontents were heated to 100° C. for 20 h. The reaction was poured into a1:1 mix of dichloromethane and water for workup, and the aqueous layerwas treated with sodium chloride before extraction with dichloromethane.The crude material was purified via silica gel chromatography utilizinga 0-10% methanol/dichloromethane gradient to deliver the desiredcompound, Compound I-320 (81 mg, 84% yield) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.75 (d, 1H), 8.10 (d, 1H), 7.42 (s, 1H),7.29-7.23 (m, 1H), 7.11-7.06 (m, 1H), 7.02 (t, 1H), 6.88 (d, 1H),6.85-6.80 (m, 1H), 5.95 (s, 2H), 4.03-3.94 (m, 2H), 3.73-3.66 (m, 1H),3.58 (d, 2H), 3.42 (d, 3H).

Compound I-321

The title compound was prepared following general procedure B, except(R)-3-(methylamino)propane-1,2-diol was the amine reactant and thecontents were heated to 100° C. for 2 d. The reaction was poured into a1:1 mix of dichloromethane and water for workup, and the aqueous layerwas treated with sodium chloride before extraction with dichloromethane.The crude material was purified via silica gel chromatography utilizinga 0-10% methanol/dichloromethane gradient to deliver the desiredcompound, Compound I-321 (88 mg, 77% yield) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.74 (d, 1H), 8.09 (d, 1H), 7.41 (s, 1H),7.28-7.22 (m, 1H), 7.10-7.05 (m, 1H), 7.04-6.99 (m, 1H), 6.87 (d, 1H),6.82 (td, 1H), 5.94 (s, 2H), 4.02-3.93 (m, 2H), 3.72-3.66 (m, 1H), 3.58(d, 2H), 3.41 (d, 3H).

Compound I-322

The title compound was prepared following general procedure B, except(S)-3-((cyclopropylmethyl)amino)propane-1,2-diol was the amine reactantand the contents were heated to 100° C. for 20 h. The reaction waspoured into a 1:1 mix of dichloromethane and water for workup, and theaqueous layer was treated with sodium chloride before extraction withdichloromethane. The crude material was purified via silica gelchromatography utilizing a 0-10% methanol/dichloromethane gradient todeliver the desired compound, Compound I-322 (39 mg, 62% yield) as awhite foam.

¹H-NMR (500 MHz, CDCl₃) δ 8.45 (d, 1H), 8.12 (d, 1H), 7.29 (s, 1H),7.24-7.19 (m, 1H), 7.05-6.97 (m, 3H), 6.57 (d, 1H), 5.99-5.94 (m, 1H),5.91-5.86 (m, 1H), 4.14 (dd, 1H), 4.02 (br. s., 1H), 3.93 (br. s., 1H),3.86 (br. s., 1H), 3.68-3.57 (m, 4H), 3.43 (ddd, 1H), 1.15-1.06 (m, 1H),0.65-0.53 (m, 2H), 0.38-0.32 (m, 1H), 0.32-0.26 (m, 1H).

Compound I-323

The title compound was prepared following general procedure B, except(S)-3-(isopropylamino)propane-1,2-diol was the amine reactant and thecontents were heated to 100° C. for 20 h. The reaction was poured into a1:1 mix of dichloromethane and water for workup, and the aqueous layerwas treated with sodium chloride before extraction with dichloromethane.The crude material was purified via silica gel chromatography utilizinga 0-50% (acetonitrile:methanol=7:1)/dichloromethane gradient to deliverthe desired compound, Compound I-323 (12 mg, 20% yield) as a whitesolid.

¹H-NMR (500 MHz, CDCl₃) δ 8.45 (d, 1H), 8.13 (d, 1H), 7.30 (s, 1H),7.25-7.19 (m, 1H), 7.06-6.98 (m, 3H), 6.58 (d, 1H), 6.00-5.94 (d, 1H),5.91-5.85 (d, 1H), 4.95 (br. s., 1H), 4.67-4.58 (m, 1H), 3.82-3.74 (m,2H), 3.70-3.60 (m, 2H), 3.59-3.49 (m, 2H), 1.32 (d, 3H), 1.29 (d, 3H).

Compound I-324

The title compound was prepared following general procedure B, except2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropan-2-ol was the aminereactant, the contents were heated to 100° C. for 20 h, and the aqueouslayer was treated with sodium chloride before extraction withdichloromethane during work up. The crude material was purified viasilica gel chromatography utilizing a 0-10% ethyl acetate/hexanegradient to deliver the desired compound, Compound I-324 (5 mg, 9%yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.48 (d, 1H), 8.36 (s, 1H), 8.26 (d, 1H),7.25-7.20 (m, 2H), 7.14 (t, 1H), 7.05-6.99 (m, 2H), 6.59 (d, 1H), 5.94(s, 2H), 5.59 (br. s., 1H), 4.12 (d, 2H).

Compound I-325

The title compound was prepared following general procedure B, except1-amino-2-methylpropan-2-ol was the amine reactant, and the contentswere heated to 100° C. for 20 h. The reaction was poured into a 1:1 mixof dichloromethane and water for workup, and the aqueous layer wastreated with sodium chloride before extraction with dichloromethane.

The crude material was purified via silica gel chromatography utilizinga 0-10% methanol/dichloromethane gradient to deliver the desiredcompound, Compound I-325 (43 mg, 93% yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.43 (d, 1H), 8.14 (d, 1H), 7.27 (s, 1H),7.21-7.15 (m, 1H), 7.04-6.98 (m, 1H), 6.95 (t, 1H), 6.84 (t, 1H), 6.59(d, 1H), 5.95 (s, 2H), 5.62 (br. s., 1H), 3.70 (s, 1H), 3.63 (d, 2H),1.31 (s, 6H).

Compound I-326

A mixture of (S)-trifluorolactic acid (1.5 equiv.) and1,1′-carbodiimidazole (1.5 equiv.) in THF was heated to 70° C. for 2 h.2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-pyrimidin-4-amine(intermediate described in WO2012/3405 A1) (1 equiv.) was added to thereaction mixture, and contents stirred at 70° C. for 3 d. The contentswere cooled to 23° C., diluted with ethyl acetate, and washed with 1NHCl solution. The organic layer was washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo. The crude material was purified viasilica gel chromatography utilizing a 0-100% ethyl acetate/hexanesgradient to deliver the desired compound, Compound I-326 (3 mg, 4%yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ 9.61 (br. s., 1H), 8.76 (d, 1H), 8.49 (d, 1H),8.16 (d, 1H), 7.47 (s, 1H), 7.25-7.21 (m, 1H), 7.11-7.03 (m, 1H), 7.00(t, 1H), 6.83 (t, 1H), 6.63 (d, 1H), 6.36 (br. s., 1H), 6.06-5.95 (m,2H), 4.69 (d, 1H).

Compound I-329 and Compound I-330

Compound I-161 was resolved by chiral separation with chiracel-ODH 20mm×250 mm semi-prep column, using a 10-90% isopropanol/hexanes gradient.Collection of the peak that eluted first and concentration in vacuoyielded Compound I-329 as a white solid. Collection of the peak thateluted second and concentration in vacuo yielded Compound-330 as a whitesolid.

¹H-NMR for Compound I-329 (500 MHz, CDCl₃) δ 8.38 (d, 1H), 8.16 (d, 1H),7.21 (s, 1H), 7.20-7.15 (m, 1H), 7.04-6.99 (m, 1H), 6.97-6.93 (m, 1H),6.89-6.84 (m, 1H), 6.48 (d, 1H), 6.06-6.00 (m, 1H), 5.93-5.88 (m, 1H),4.76 (d, 1H), 4.15 (d, 1H), 3.54-3.43 (m, 1H), 2.09-1.98 (m, 1H),1.91-1.82 (m, 1H), 1.81-1.64 (m, 3H), 1.17 (d, 3H).

¹H-NMR for Compound I-330 (500 MHz, CD₃OD) δ 8.78-8.74 (d, 1H), 8.21 (d,1H), 7.45 (s, 1H), 7.30-7.23 (m, 1H), 7.11-7.06 (m, 1H), 7.03 (t, 1H),6.86 (d, 1H), 6.83 (t, 1H), 5.95 (s, 2H), 5.04 (d, 1H), 4.37 (d, 1H),3.69 (td, 1H), 2.16-2.07 (m, 1H), 1.93-1.86 (m, 1H), 1.82-1.70 (m, 2H),1.52 (qd, 1H), 1.21 (d, 3H).

Compound I-331 and Compound I-332

A mixture of Compound I-329 and 1,1′-carbodiimidazole (1 equiv.) in DCMwas heated to 45° C. until all starting material was consumed asobserved on the LC/MS. Cyclopropanesulfonamide (4 equiv.) and DBU (2equiv.) was added to the reaction mixture, and contents stirred at 45°C. for an additional 30 min. The contents were cooled to 23° C.,quenched with 1N HCl solution, and the layers were separated. Theaqueous layer was extracted with dichloromethane (×2), and the organicportions were combined and washed with brine. The mixture was dried overNa₂SO₄, filtered, and concentrated in vacuo. The crude material waspurified via silica gel chromatography utilizing a 0-20%(acetonitrile:methanol=7:1)/dichloromethane gradient to deliver CompoundI-331 (40 mg, 13% yield) as a white solid, and Compound I-332 (3 mg, 1%yield) as a white solid.

1H-NMR for Compound I-331 (400 MHz, DMSO-d₆) δ 12.09 (s, 1H), 9.14 (d,1H), 8.38 (d, 1H), 7.25-7.18 (m, 1H), 7.37-7.29 (m, 1H), 7.55 (s, 1H),7.12-7.06 (m, 2H), 6.87-6.80 (m, 1H), 5.94-5.84 (m, 2H), 4.73 (d, 1H),4.23 (br. s., 1H), 3.66-3.54 (m, 1H), 2.94-2.85 (m, 1H), 2.38 (d, 1H),1.89-1.81 (m, 1H), 1.68-1.51 (m, 3H), 1.15 (d, 3H), 0.97-0.92 (m, 2H),0.89-0.84 (m, 2H).

¹H-NMR for Compound I-332 (400 MHz, DMSO-d₆) δ 11.97 (s, 1H), 9.14 (d,1H), 8.41 (d, 1H), 7.65 (s, 1H), 7.37-7.28 (m, 1H), 7.26-7.17 (m, 1H),7.14-7.05 (m, 2H), 6.88-6.79 (m, 1H), 5.97-5.86 (m, 2H), 4.70 (d, 1H),4.13 (d, 1H), 3.83-3.72 (m, 1H), 2.97-2.87 (m, 1H), 2.10 (d, 1H), 1.85(d, 1H), 1.74-1.60 (m, 2H), 1.53-1.39 (m, 1H), 1.16 (d, 3H), 1.05-0.93(m, 3H), 0.87-0.78 (m, 1H).

Compound I-333

A mixture of3-(3-(4-chloropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole(synthesis of which is described in the procedure towards Compound I-24)(1 equiv.), (2R,3S)-3-methylpiperidine-2-carboxylic acid (as the(1S)-(+)-camphorsulfonic acid salt, 1 equiv.), and triethylamine (1equiv.) was heated to 110° C. for 48 h as a solution in dioxane/water(2:1). The contents were cooled to 23° C., and partitioned between a 1:1mixture of dichloromethane and 1N HCl solution. The layers wereseparated, and the aqueous layer was extracted with dichloromethane(×2), and the organic portions were combined and washed with brine. Themixture was dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude material was purified via silica gel chromatography utilizing a0-20% (acetonitrile:methanol 7:1)/dichloromethane gradient to deliverthe desired compound, Compound I-333 (10 mg, 4% yield) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 12.64 (br. s., 1H), 9.10 (d, 1H), 8.30 (d,1H), 7.55 (br. s., 1H), 7.38-7.29 (m, 1H), 7.27-7.16 (m, 2H), 7.15-7.06(m, 1H), 6.83 (d, 2H), 5.90 (s, 2H), 3.21 (s, 1H), 1.94 (br. s., 1H),1.89-1.80 (m, 1H), 1.69-1.35 (m, 5H), 1.13 (d, 3H).

Compound I-334

The title compound was prepared following general procedure B, except2-amino-2-(hydroxymethyl)propane-1,3-diol was the amine reactant and thecontents were heated to 110° C. for 20 h. The crude material waspurified via silica gel chromatography utilizing a 0-20%(acetonitrile:methanol=7:1)/dichloromethane gradient to deliver thedesired compound, Compound I-334 (185 mg, 72% yield) as an off-whitesolid.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.10 (d, 1H), 8.24 (d, 1H), 7.46 (s, 1H),7.36-7.29 (m, 1H), 7.25-7.18 (m, 2H), 7.10 (td, 1H), 6.91-6.84 (m, 1H),6.36 (s, 1H), 5.86 (s, 2H), 4.95 (br. s., 3H), 3.76-3.72 (m, 6H).

Compound I-335

The title compound was prepared following general procedure B, except(S)-2-amino-3-hydroxypropanamide was the amine reactant and the contentswere heated to 110° C. for 20 h. The crude material was purified viasilica gel chromatography utilizing a 0-20%(acetonitrile:methanol=7:1)/dichloromethane gradient to deliver thedesired compound, Compound I-335 (170 mg, 37% yield) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.14 (d, 1H), 8.56 (br. s., 1H), 8.41 (d,1H), 7.70 (s, 2H), 7.37-7.31 (m, 1H), 7.29-7.19 (m, 3H), 7.14-7.08 (m,1H), 6.86 (t, 1H), 5.94 (s, 2H), 4.87-4.80 (m, 1H), 3.89-3.78 (m, 2H),3.06 (qd, 1H).

Compound I-336

A solution of Compound I-112 (1 equiv.) in DMF was treated successivelywith Hunig's base (3 equiv.) and HATU (1 equiv.). After stirring for 5minutes, serinol (1.5 equiv.) was added, and the reaction was stirred at23° C. for 20 h. The mixture was partitioned between a 1:1 mixture ofdichloromethane and 1N HCl solution. The layers were separated, and theaqueous layer was extracted with dichloromethane (×2). The combinedorganic portions were washed with brine. The mixture was dried overNa₂SO₄, filtered, and concentrated in vacuo. The crude material waspurified via silica gel chromatography utilizing a 0-20%(acetonitrile:methanol=7:1)/dichloromethane gradient to deliver thedesired compound, Compound I-336 (22 mg, 26% yield) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.14 (d, 1H), 8.96 (br. s., 1H), 8.45 (d,1H), 8.17 (d, 1H), 7.85 (s, 1H), 7.38-7.29 (m, 1H), 7.28-7.18 (m, 2H),7.14-7.07 (m, 1H), 6.86 (t, 1H), 5.96 (s, 2H), 4.94-4.86 (m, 1H),3.86-3.78 (m, 2H), 3.74-3.65 (m, 1H), 3.64-3.53 (m, 1H), 3.53-3.46 (m,1H), 3.45-3.40 (m, 2H), 3.40-3.34 (m, 2H), 3.16-3.04 (m, 1H).

Compound I-337

The title compound was prepared following general procedure B, except3-amino-1,1,1-trifluoropropan-2-ol (5 equiv.) was the amine reactant andthe contents were heated to 110° C. for 20 h. The crude material waspurified via silica gel chromatography utilizing a 0-20%(acetonitrile:methanol=7:1)/dichloromethane gradient to deliver thedesired compound, Compound I-337 (70 mg, 53% yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.76 (d, 1H), 8.10 (d, 1H), 7.38 (s, 1H),7.30-7.23 (m, 1H), 7.08 (dd, 1H), 7.05-7.00 (m, 1H), 6.88-6.82 (m, 2H),5.95 (s, 2H), 4.40-4.30 (m, 1H), 3.99 (dd, 1H), 3.70 (dd, 1H).

Compound I-339

The title compound was prepared in 2 steps:

Step 1: Synthesis of methyl2-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylate

This intermediate was prepared following general procedure B, exceptmethyl 1,2,3,4-tetrahydroisoquinoline-8-carboxylate (as the HCl salt)was the amine reactant. Work up delivered the desired methyl ester,methyl2-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylate(Compound I-338, 55 mg, 97% yield) as an orange oil, which was carriedon without further purification.

Step 2: Synthesis of Compound I-339

A solution of methyl2-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylateand lithium hydroxide hydrate (1.5 equiv.) in tetrahydrofuran, water,and methanol (3:1:1 ratio) was stirred at 23° C. for 21 h. Additionalbase (1.5 equiv.) was added, and the solution was stirred for 24 h. Thesolution was poured into water, 1 N sodium hydroxide, anddichloromethane (10:1:10 ratio). The layers were separated and theaqueous layer was acidified to pH 1. The aqueous layer was extractedwith dichloromethane, dried over magnesium sulfate, filtered, and thesolvent was removed in vacuo to deliver the desired compound, CompoundI-339 (9 mg, 17% yield over 2 steps) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 13.14 (s, 1H), 9.12 (d, 1H), 8.32 (d, 1H),7.79-7.77 (m, 1H), 7.48 (s, 1H), 7.43-7.41 (d, 1H), 7.34-7.30 (m, 2H),7.24-7.20 (m, 2H), 7.11 (dt, 1H), 6.85 (dt, 1H), 5.89 (s, 2H), 5.34 (d,2H), 4.07 (t, 2H), 3.04 (t, 2H).

Compound I-341

The title compound was prepared in 3 steps:

Step 1: Synthesis ofcis-1-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)-3-methylpiperidine-2-carboxamide(Compound I-340)

To a solution of Compound I-161 and triethylamine (1 equiv.) at 0° C. intetrahydrofuran was added ethyl chloroformate (1.05 equiv.) dropwiseover 5 minutes. The reaction mixture was maintained at 0° C. for 45 min,and then ammonium hydroxide (7 equiv.) was added. The solution wasimmediately warmed to 23° C. and stirred for an additional 15 hours. Thereaction mixture was diluted with ethyl acetate and saturated aqueousammonium chloride. The layers were separated and the aqueous layer wasextracted with ethyl acetate. The organics were dried over magnesiumsulfate, filtered, and the solvent was removed in vacuo. Purificationvia silica gel chromatography (20-100% hexanes in ethyl acetategradient) providedcis-1-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)-3-methylpiperidine-2-carboxamide(Compound I-340, 270 mg, 54% yield) as a yellow foam.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.46 (d, 1H), 8.17 (d, 1H), 7.23 (s, 1H),7.22-7.17 (m, 1H), 7.12-6.91 (m, 3H), 6.59 (d, 1H), 6.06-5.76 (m, 2H),5.34 (br. s., 1H), 4.76 (d, 1H), 4.18 (d, 1H), 3.32 (ddd, 1H), 2.64-2.50(m, 1H), 2.08-1.79 (m, 2H), 1.65-1.50 (m, 1H), 1.49-1.37 (m, 1H), 1.15(d, 1H), 1.05 (d, 3H).

Step 2: Synthesis ofcis-1-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)-3-methylpiperidine-2-carbonitrile

To a 0° C. solution ofcis-1-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)-3-methylpiperidine-2-carboxamidein pyridine was added trifluoroacetic anhydride (2 equiv.) dropwise over5 minutes. After stirring for 45 min at 0° C., the solution was warmedto room temperature and then immediately poured into dichloromethane andsaturated aqueous ammonium chloride. The layers were separated and theaqueous layer was extracted with dichloromethane. The organics weredried over magnesium sulfate, filtered, and the solvent was removed invacuo. Purification via silica gel chromatography (10-75% hexanes inethyl acetate gradient) gavecis-1-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)-3-methylpiperidine-2-carbonitrile(215 mg, 83% yield) as a white foam.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.44 (d, 1H), 8.31 (d, 1H), 7.30 (s, 1H),7.22-7.11 (m, 1H), 7.06-6.91 (m, 2H), 6.82 (t, 1H), 6.59 (d, 1H), 5.95(s, 2H), 5.40 (s, 1H), 4.35 (d, 1H), 3.32 (td, 1H), 2.48-2.35 (m, 1H),2.20-1.84 (m, 2H), 1.61-1.76 (m, 2H), 1.17 (d, 3H).

Step 3: Synthesis of Compound I-341

A suspension ofcis-1-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)-3-methylpiperidine-2-carbonitrile,ammonia hydrochloride (5 equiv.), and sodium azide (5 equiv.) inN,N-dimethylformamide was heated to 90° C. for 60 hours. The solutionwas diluted with ethyl acetate and aqueous 1 N hydrochloric acidsolution. The layers were separated and the aqueous layer was extractedwith ethyl acetate. The organics were washed with water and brine, driedover magnesium sulfate, filtered, and the solvent was removed in vacuo.The crude solid was suspended in dichloromethane and filtered to giveproduct contaminated with side product. The filtrate was concentrated invacuo and the resulting solid was suspended in diethyl ether andfiltered to deliver the desired compound, Compound I-341 (135 mg, 57%yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.51 (d, 1H), 8.15 (d, 1H), 7.29 (s, 1H),7.25-7.20 (m, 2H), 7.04-6.99 (m, 2H), 6.63 (d, 1H), 6.09 (d, 1H), 6.00(d, 1H), 5.18 (d, 1H), 3.98 (dd, 1H), 3.31 (dt, 1H), 2.81-2.75 (m, 1H),2.54-2.46 (m, 1H), 2.13-2.02 (m, 1H), 1.80-1.75 (m, 1H), 1.60-1.51 (m,1H), 1.11 (d, 3H).

Compound I-342

The title compound was prepared following general procedure B, except1-((methylamino)methyl)cyclobutanecarboxylic acid (as the TFA salt) wasthe amine reactant. Work up delivered the desired compound, CompoundI-342 (64 mg, quantitative yield) as a yellow solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.81 (d, 1H), 8.29 (d, 1H), 7.56 (m, 1H),7.32-7.26 (m, 1H), 7.11-7.02 (m, 2H), 6.96-6.92 (m, 2H), 5.98 (s, 2H),4.37 (s, 2H), 3.48 (d, 3H), 2.51-2.44 (m, 2H), 2.25-2.16 (m, 2H),2.09-1.93 (m, 2H).

Compound I-343

A suspension of5-fluoro-2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-pyrazol-3-yl)pyrimidin-4-ol (intermediate previously described in WO2013/101830 A1)in phosphoryl chloride (20 equiv.) was heated to 60° C. for 2 h. Thephosphoryl chloride was removed under a stream of nitrogen and theresulting residue dissolved in dioxane and water (2:1 ratio). Followingthe addition of 1-((methylamino)methyl)cyclopropanecarboxylic acidhydrochloride (3 equiv.), and triethylamine (10 equiv.), the solutionwas heated to 90° C. for 4 h. The solution was diluted withdichloromethane and 1 N hydrochloric acid solution. The layers wereseparated and the aqueous layer extracted with dichloromethane. Theorganics were dried over magnesium sulfate, filtered, and the solventwas removed in vacuo. Purification via silica gel chromatography (0-5%methanol in dichloromethane gradient) delivered the desired compound,Compound I-343 (17 mg, 52% yield) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 12.34 (s, 1H), 8.23 (d, 1H), 7.98 (d, 1H),7.92 (d, 1H), 7.35 (s, 1H), 7.34-7.29 (m, 1H), 7.23-7.18 (m, 1H), 7.10(dt, 1H), 6.93 (dt, 1H), 6.02 (s, 2H), 4.00 (s, 2H), 3.24 (d, 3H),1.15-1.12 (m, 2H), 1.03-1.01 (m, 2H).

Compound I-344

To a solution of Compound I-248 in dichloromethane was addedcarbonyldiimidazole (1.2 equiv.). The resulting mixture was stirred at40° C. for 45 min. The solution was cooled to 23° C. and1,8-diazabicyclo[5.4.0]undec-7-ene (2 equiv.) was added, followed bycyclopropanesulfonamide (3 equiv.). After stirring for 16 h, thesolution was poured into dichloromethane and 1N hydrochloric acidsolution. The layers were separated and the aqueous layer was extractedwith dichloromethane. The organics were dried over magnesium sulfate,filtered, and the solvent was removed in vacuo. Initial purification viasilica gel chromatography (methanol in dichloromethane) gave impureproduct. The impure residue was brought up in diethyl ether, and hexaneswere added until the solution became cloudy. After stirring for 20 min,the solid was filtered off to deliver the desired compound, CompoundI-344 (29 mg, 48% yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.44 (d, 1H), 8.09 (d, 1H), 7.23-7.17 (m, 2H),7.03-6.97 (m, 3H), 6.51 (d, 1H), 5.95 (s, 2H), 3.96 (dd, 1H), 3.69-3.63(m, 1H), 3.32 (d, 3H), 2.90-2.81 (m, 2H), 2.03-1.96 (m, 1H), 1.18-1.14(m, 2H), 1.03 (dd, 6H), 0.92-0.90 (m, 2H).

Compound I-345

A suspension of5-fluoro-2-(1-(2-fluorobenzyl)-5-(thiazol-4-yl)-1H-pyrazol-3-yl)pyrimidin-4-ol(intermediate previously described in WO2013/101830 A1) in phosphorylchloride (50 equiv.) was heated to 60° C. for 2 h. The phosphorylchloride was removed under a stream of nitrogen, and the resultingresidue was dissolved in dioxane and water (2:1) and treated with1-((methylamino)methyl)cyclopropanecarboxylic acid hydrochloride (3equiv.), followed by triethylamine (10 equiv.). The resulting solutionwas heated to 90° C. for 7.5 days. The reaction mixture was poured intodichloromethane and 1N hydrochloric acid solution. The layers wereseparated and the aqueous layer was extracted with dichloromethane. Theorganics were dried over magnesium sulfate, filtered, and the solventwas removed in vacuo. Purification by silica gel chromatography (0-10%methanol in dichloromethane gradient) provided Compound I-345 (2.8 mg,11% yield) as a white film.

¹H-NMR (400 MHz, CD₃OD) δ 9.03 (d, 1H), 8.07 (d, 1H), 7.89 (d, 1H),7.24-7.19 (m, 2H), 7.04-6.96 (m, 2H), 6.81 (t, 1H), 5.94 (s, 2H), 4.13(s, 2H), 3.34 (d, 3H), 1.28-1.25 (m, 2H), 1.08-1.05 (m, 2H).

Compound I-346

The title compound was prepared following general procedure B, except3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (asthe HCl salt) was the amine reactant. Following workup, the crude solidwas suspended in diethyl ether and filtered to deliver the desiredcompound, Compound I-346 (57 mg, 84% yield) as a tan solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.84 (d, 1H), 8.41 (d, 1H), 7.63 (s, 1H),7.33-7.28 (m, 1H), 7.13-7.04 (m, 2H), 6.98-6.95 (m, 2H), 6.03 (s, 2H),5.19 (s, 2H), 4.42 (t, 2H), 3.09 (t, 2H).

Compound I-347

The title compound was prepared following general procedure B, exceptracemic syn-piperidine-3,4,5-triol was the amine reactant. Uponcompletion of the reaction by LC/MS, the solvent was removed in vacuo.Methanol was added and the resulting suspension was filtered to deliverthe desired compound, Compound I-347 (20 mg, 11% yield) as a solid.

1H-NMR (400 MHz, DMSO-d₆) δ 9.09 (d, 1H), 8.28 (d, 1H), 7.52 (s, 1H),7.35-7.29 (m, 1H), 7.24-7.21 (m, 2H), 7.09 (t, 1H), 6.80 (t, 1H), 5.90(s, 2H), 4.92 (d, 2H), 4.80 (d, 1H), 4.15-4.11 (m, 2H), 3.83-3.80 (m,1H), 3.58-3.53 (m, 2H), 3.27-3.21 (m, 2H).

Compound I-348

The title compound was prepared following general procedure B, except1,3-diaminopropan-2-ol was the amine reactant, and contents were heatedto 40° C. for 45 min. Upon completion of the reaction by LC/MS, dioxanewas removed in vacuo and enough methanol was added to solubilize thecrude mixture. Purification via reverse-phase HPLC (5-75% acetonitrilein water w/0.1% trifluoroacetic acid, 20 min gradient) delivered thedesired compound, Compound I-348 (58 mg, 80% yield) as a pink foam.

¹H-NMR (400 MHz, CD₃OD) δ 8.82 (d, 1H), 8.27 (d, 1H), 7.62 (s, 1H),7.32-7.27 (m, 1H), 7.12-7.03 (m, 2H), 6.95-6.91 (m, 2H), 6.02 (d, 1H),5.97 (d, 1H), 4.21-4.15 (m, 1H), 3.85-3.77 (m, 2H), 3.22-3.18 (dd, 1H),2.96 (dd, 1H).

Compound I-349

To a solution of Compound I-340 and triethylamine (5 equiv.) indichloromethane at 0° C. was added methanesulfonyl chloride (1 equiv.)dropwise. After stirring for 45 min, saturated aqueous sodiumbicarbonate was added and the reaction mixture was warmed to 23° C.Dichloromethane was added and the layers were separated. The aqueouslayer was extracted with dichloromethane and the organics were driedover magnesium sulfate, filtered, and the solvent was removed in vacuo.Purification via reverse phase HPLC (5-50% acetonitrile in water w/0.1%TFA) delivered the desired compound, Compound I-349 (6 mg, 25% yield) asa white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.78 (d, 1H), 8.24 (d, 1H), 7.70 (s, 1H),7.31-7.25 (m, 1H), 7.11-7.02 (m, 3H), 6.92-6.88 (m, 1H), 6.04 (s, 2H),4.10-4.01 (m, 2H), 3.61-3.56 (m, 1H), 3.18-3.17 (m, 2H), 2.95 (s, 3H).

Compound I-350

The title compound was prepared following general procedure B, exceptracemic cis-piperidine-3,4-diol (as the HCl salt) was the aminereactant. The crude material was purified via reverse phase HPLC (5-50%acetonitrile in water w/0.1% TFA, 20 min gradient) delivered the desiredcompound, Compound I-350 (1.7 mg, 3% yield) as a clear film.

¹H-NMR (400 MHz, CD₃OD) δ 8.81 (m, 1H), 8.28 (d, 1H), 7.64 (s, 1H),7.32-7.26 (m, 1H), 7.12-7.03 (m, 2H), 6.97-6.93 (m, 2H), 6.01 (s, 2H),4.52 (br s, 2H), 4.38 (dd, 1H), 3.97-3.90 (m, 2H), 3.77-3.72 (m, 1H),2.02-1.97 (m, 1H), 1.90-1.86 (m, 1H).

Compound I-351

The title compound was prepared following general procedure B, excepttert-butyl 3-(aminomethyl)-3-hydroxyazetidine-1-carboxylate was theamine reactant, and the reaction was run as a solution in dioxane. Ethylacetate was used as solvent during work up. The crude material waspurified via silica gel chromatography (0-5% methanol in dichloromethanegradient) to deliver the desired compound, Compound I-351 (144 mg,quantitative yield) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.76 (d, 1H), 8.11 (d, 1H), 7.44 (s, 1H),7.30-7.25 (m, 1H), 7.12-7.01 (m, 2H), 6.92 (d, 1H), 6.81 (t, 1H), 5.97(s, 2H), 4.09 (d, 2H), 3.93 (br s, 2H), 3.78 (d, 2H), 1.40 (s, 9H).

Compound I-352

The title compound was prepared following general procedure B, except3-(aminomethyl)oxetan-3-ol was the amine reactant, and the reaction wasrun as a solution in dioxane. After stirring for 1.5 h at 90° C., 2additional equivalents of oxetane were added and the reaction mixturewas stirred at 90° C. for 3 h. The reaction solution was then pouredinto ethyl acetate and aqueous 1N hydrochloric acid solution. The layerswere separated, and the aqueous layer was extracted with 5:1dichloromethane/isopropyl alcohol. The organics were dried overmagnesium sulfate, filtered, and the solvent was removed in vacuo.Purification by reverse-phase HPLC (5-75% acetonitrile in water, 0.1%TFA, 15 min gradient) delivered Compound I-352 (25 mg, 53% yield) as awhite solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.83 (d, 1H), 8.29 (d, 1H), 7.65 (s, 1H),7.32-7.28 (m, 1H), 7.13-7.05 (m, 2H), 6.99-6.94 (m, 2H), 6.02 (s, 2H),4.05 (d, 1H), 3.98 (d, 1H), 3.78-3.63 (m, 4H).

Compound I-353

To a solution of Compound I-351 at 23° C. in dichloromethane was addedtrifluoroacetic acid (30 equiv.) in a single portion. After stirring for30 min, the solution was concentrated in vacuo and the resulting residuewas brought up in diethyl ether. The solid was filtered to deliver thedesired compound, Compound I-353 (160 mg, quantitative yield) as a tansolid.

¹H-NMR (400 MHz, CD₃OD) δ 8.83 (m, 1H), 8.29-8.25 (m, 1H), 7.60-7.57 (m,1H), 7.33-7.28 (m, 1H), 7.14-7.04 (m, 2H), 6.93-6.89 (m, 2H), 6.00 (s,2H), 4.31 (d, 2H), 4.05 (m, 2H), 3.97 (d, 2H).

Compound I-354

The title compound was prepared following general procedure B, exceptN-(1-(aminomethyl)cyclopropyl)-1,1,1-trifluoromethanesulfonamide (as theHCl salt) was the amine reactant. The crude material was purified viasilica gel chromatography (0-50% ethyl acetate in hexanes gradient) todeliver the desired compound, Compound I-354 (15 mg, 25% yield) as awhite solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.75 (d, 1H), 8.08 (d, 1H), 7.50 (s, 1H),7.28-7.24 (m, 1H), 7.10-7.07 (m, 1H), 7.04-7.01 (m, 1H), 6.83-6.80 (m,2H), 5.96 (s, 2H), 3.85 (s, 2H), 1.06-1.04 (m, 2H), 0.99-0.96 (m, 2H).

Compound I-355

The title compound was prepared following general procedure B, except2-(aminomethyl)-3,3,3-trifluoropropane-1,2-diol was the amine reactant,and the reaction was run as a solution in dioxane. After workup withethyl acetate and 1N hydrochloric acid solution, purification via silicagel chromatography (0-10% methanol in dichloromethane gradient)delivered the desired compound, Compound I-355 (17 mg, 36% yield) as awhite solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.75 (d, 1H), 8.15 (d, 1H), 7.39 (s, 1H),7.28-7.23 (m, 1H), 7.09-7.01 (m, 2H), 6.88-6.85 (m, 2H), 5.96 (d, 1H),5.93 (d, 1H), 4.02 (d, 1H), 3.90 (d, 1H), 3.75 (d, 1H), 3.62 (d, 1H).

Compound I-356

The title compound was prepared following general procedure B, except(S)-3-aminopyrrolidin-2-one (as the HCl salt) was the amine reactant.The crude residue was in suspended in 3:1 diethyl ether anddichloromethane. The resulting solid was filtered to deliver the desiredcompound, Compound I-356 (10 mg, 22% yield) as a tan solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.83 (s, 1H), 8.34 (m, 1H), 7.63-7.62 (m, 1H),7.33-7.29 (m, 1H), 7.13-7.05 (m, 2H), 6.98-6.96 (m, 2H), 6.03 (s, 2H),5.36-5.32 (m, 1H), 3.56-3.49 (m, 2H), 2.66-2.61 (m, 1H), 2.38-2.30 (m,1H).

Compound I-357

The title compound was prepared in 5 steps:

Step 1: Synthesis of tert-butyl3-(2,2,2-trifluoro-1-hydroxyethyl)azetidine-1-carboxylate

To a 0° C. solution of tert-butyl 3-formylazetidine-1-carboxylate (1equiv.) and trimethyl(trifluoromethyl)silane (1.4 equiv.) intetrahydrofuran was added tetrabutylammonium fluoride (1 M solution intetrahydrofuran, 1.1 equiv.) over the course of 10 min. The solution waswarmed immediately to 23° C. and stirred for 19 h. The reaction mixturewas poured into 1N hydrochloric acid solution and diethyl ether. Thelayers were separated and the aqueous layer was extracted with diethylether. The organics were washed with saturated aqueous sodium chloride,dried over magnesium sulfate, filtered, and the solvent was removed invacuo to give tert-butyl3-(2,2,2-trifluoro-1-hydroxyethyl)azetidine-1-carboxylate (558 mg, 79%yield) as a pale yellow solid.

Step 2: Synthesis of tert-butyl3-(2,2,2-trifluoroacetyl)azetidine-1-carboxylate

To tert-butyl 3-(2,2,2-trifluoro-1-hydroxyethyl)azetidine-1-carboxylate(1 equiv.) in dichloromethane at 0° C. was added Dess-Martin periodinane(2 equiv.) in a single portion. After 5 minutes at 0° C., the solutionwas warmed to 23° C. After two hours, LC/MS showed complete conversion.The reaction mixture was poured into 5:1 saturated aqueous sodiumdithionite and saturated aqueous sodium bicarbonate (75 mL). Afterstirring for 10 minutes, dichloromethane was added and the layers wereseparated. The aqueous layer was extracted with dichloromethane, theorganics were dried over magnesium sulfate, filtered, and the solventwas removed in vacuo to give tert-butyl3-(2,2,2-trifluoroacetyl)azetidine-1-carboxylate (263 mg, 92% yield) asa white greasy solid that was a mixture of ketone and hydrate by ¹H-NMR.

Step 3: Synthesis of tert-butyl3-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)azetidine-1-carboxylate

To a 0° C. solution of tert-butyl3-(2,2,2-trifluoroacetyl)azetidine-1-carboxylate (1 equiv.) andtrimethyl(trifluoromethyl)silane (1.4 equiv.) in tetrahydrofuran wasadded tetrabutylammonium fluoride (1.1 equiv.) as a 1M solution intetrahydrofuran dropwise over 5 min. The solution was warmed immediatelyto 23° C. and stirred for 2.5 d. The solution was then poured into ethylacetate and aqueous 1N hydrochloric acid solution. The layers wereseparated and the aqueous layer was extracted with ethyl acetate (2×).The organics were washed with saturated aqueous sodium chloride, driedover magnesium sulfate, filtered, and the solvent was removed in vacuo.Purification via silica gel chromatography (0-60% ethyl acetate inhexanes gradient) provided tert-butyl3-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)azetidine-1-carboxylate(24 mg, 7% yield) as an oily solid.

Step 4: Synthesis of 2-(azetidin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol

tert-butyl3-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)azetidine-1-carboxylatewas stirred in trifluoroacetic acid and dichloromethane (1:2 ratio) for1.5 h. The solution was then concentrated in vacuo to provide2-(azetidin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol as the TFA salt.

Step 5: Synthesis of Compound I-357

The title compound was prepared following general procedure B, except2-(azetidin-3-yl)-1,1,1,3,3,3-hexafluoropropan-2-ol (as the TFA salt,1.5 equiv.) was the amine reactant. The crude residue was brought up in1:1 dichloromethane and diethyl ether and the solid was filtered off andwashed with additional diethyl ether to deliver the desired compound,Compound I-357 (17 mg, 64% yield) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ 8.83 (d, 1H), 8.27 (d, 1H), 7.62 (s, 1H),7.35-7.30 (m, 1H), 7.15-7.07 (m, 2H), 7.00-6.96 (m, 2H), 6.05 (s, 2H),4.82-4.70 (m, 4H), 3.79 (quint, 1H).

Compound I-359

This compound was prepared in two steps

Step 1: Synthesis of Ester I-358

The title compound was prepared following general procedure B, except1-aminomethylcyclopropanol (2 equiv.) was the amine reactant, notriethylamine was used, and contents were heated to 100° C. for 96 h asa solution in dioxane/water (3:1). Ethyl acetate was the solvent usedfor work up. The crude material was first purified via silica gelchromatography utilizing a 0-100% ethyl acetate/hexanes gradient, thenby reverse phase HPLC (water/acetonitrile with 0.1% trifluoroaceticacid). The water/acetonitrile fractions containing product were treatedwith excess 10% NaHCO₃ (aq), concentrated to 5 mL, then extracted withethyl acetate to recover the neutral material to deliver the desiredcompound, Compound I-358 (32 mg 28% yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.42 (d, 1H), 8.11 (m, 1H), 7.24 (s, 1H), 7.15(m, 1H), 6.99 (m, 1H), 6.94 (m, 1H), 6.85 (m, 1H), 6.56 (d, 1H), 5.93(s, 2H), 5.63 (m, 1H), 4.77 (m, 1H), 3.74 (d, 2H), 0.86 (m, 2H), 0.65(m, 2H).

Step 2: Synthesis of Compound I-359

Compound I-358 was dissolved in tetrahydrofuran at room temperature, andtriethylamine (3 equiv.) and ethyl chloroformate (2 equiv.) were addedin succession. Contents were allowed to stir for 1 h at roomtemperature. The mixture was diluted with ethyl acetate, washed withwater (3×) then dried over sodium sulfate, filtered and concentrated invacuo. The resulting residue was redissolved in tetrahydrofuran, treatedwith sodium borohydride (6 equiv.), and stirred for 1 h. This mixturewas diluted with ethyl acetate, washed with water (3×), then dried oversodium sulfate, filtered and concentrated in vacuo. The crude materialwas purified via silica gel chromatography utilizing a 10-80% ethylacetate/hexanes gradient to deliver the desired compound, Compound I-359(11 mg, 76% yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.41 (d, 1H), 8.11 (d, 1H), 7.28 (s, 1H), 7.16(m, 1H), 7.00 (m, 1H), 6.95 (m, 1H), 6.87 (m, 1H), 6.54 (d, 1H), 5.93(s, 2H), 5.53 (m, 1H), 4.61 (m, 1H), 3.60 (d, 2H), 3.35 (d, 2H), 0.53(m, 4H).

Compound I-360

The title compound was prepared following general procedure B, except1-(4-aminophenyl)cyclopropanecarboxylic acid (1 equiv.) was the aminereactant, 20 equivalents of triethylamine was used, and contents wereheated to 100° C. for 18 h as a solution in dioxane/water (3:1). Ethylacetate was the solvent used for work up. The crude material waspurified via silica gel chromatography utilizing a 5-95% ethylacetate/hexanes gradient to deliver the desired compound, Compound I-360(11 mg, 9% yield) as a white solid.

¹H-NMR (400 MHz, acetone-d₆) δ 8.89 (d, 1H), 8.81 (br d, 1H), 8.30 (d,1H), 8.03 (d, 2H), 7.48 (s, 1H), 7.39 (d, 2H), 7.30 (m, 1H), 7.15 (m,1H), 7.10 (m, 1H), 7.07 (d, 1H), 7.05 (m, 1H), 5.98 (s, 2H), 1.53 (m,2H), 1.18 (m, 2H).

Compound I-361

The title compound was synthesized in 3 steps:

Step 1: Synthesis of tert-butyl methyl(2-oxo-2-(phenylsulfonamido)ethyl)carbamate

To a solution of 1,1′-carbonyldiimidazole (1.2 equiv.) indichloromethane was added 2-((tert-butoxycarbonyl)(methyl)amino)aceticacid (1 equiv.). The mixture was stirred at 23° C. until gas evolutionceased. To this mixture were added benzenesulfonamide (3 equiv.) and DBU(1 equiv.). The mixture was stirred at 23° C. for 1 h. The mixture wasdiluted with dichloromethane and washed with water. The organic layerwas dried, filtered and evaporated to give a white solid. Purificationvia silica gel chromatography (0 to 80% ethyl acetate in hexanesgradient) delivered tert-butyl methyl(2-oxo-2-(phenylsulfonamido)ethyl)carbamate (1.3 g) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 7.91-7.95 (m, 2H), 7.59-7.65 (m, 3H), 3.86(s, 2H), 2.82-2.88 (m, 3H), 1.20 (s, 9H).

Step 2: Synthesis of 2-(methylamino)-N-(phenylsulfonyl)acetamidehydrochloride

A mixture of tert-butylmethyl(2-oxo-2-(phenylsulfonamido)ethyl)carbamate (1 equiv.) and HCl[4.0 M in 1,4-dioxane] was stirred at 23° C. for 24 h. The mixture wasconcentrated to give 2-(methylamino)-N-(phenylsulfonyl)acetamidehydrochloride (3.2 g) as a cream colored solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.04-8.07 (m, 2H), 7.57-7.64 (m, 3H), 3.88(s, 2H), 2.67 (s, 3H).

Step 3: Synthesis of Compound I-31

The title compound was prepared following general procedure B, except2-(methylamino)-N-(phenylsulfonyl)acetamide hydrochloride was the aminereactant, 6 equivalents of triethylamine was used, and contents wereheated to 85° C. as a solution in dioxane/water (4:1) for 24 h. Themixture was cooled to 23° C. and diluted with ethyl acetate. The organiclayer was washed with saturated solution of ammonium chloride, dried,filtered and evaporated to give a solid. The solid was purified bysilica gel chromatography (0 to 100% ethyl acetate in hexanes gradient)to deliver the desired compound, Compound I-361 (6.5 mg, 14% yield forstep 3) as a light yellow solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.79 (d, 1H), 8.12 (d, 1H), 7.91-7.96 (m,2H), 7.43-7.49 (m, 1H), 7.25-7.37 (m, 4H), 7.03-7.14 (m, 2H), 6.95 (d,1H), 6.85-6.91 (m, 1H), 5.97 (s, 2H), 4.30 (s, 2H), 3.39 (d, 3H).

Compound I-363

The title compound was prepared following general procedure B, exceptpiperidine-4-sulfonic acid (2 equiv.) was the amine reactant, 2equivalents of triethylamine was used, and contents were heated to 70°C. as a solution in dioxane/water (1:1) for 2 h. Ethyl acetate was usedas the extraction solvent during work up. The organic layer was dried,filtered, and concentrated in vacuo to deliver the desired compound,Compound I-363 (102 mg, 69% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.12 (d, 1H), 8.41 (d, 1H), 7.72 (s,1H), 7.28-7.39 (m, 2H), 7.18-7.27 (m, 1H), 7.11 (t, 1H), 6.85 (t, 1H),5.95 (s, 2H), 4.65 (d, 2H), 3.21 (t, 2H), 2.61-2.72 (m, 1H), 2.02-2.12(m, 2H), 1.52-1.70 (m, 2H).

Compound I-364

The title compound was prepared following general procedure B, except4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (as the HCl salt, 2equiv.) was the amine reactant, 4 equivalents of triethylamine was used,and contents were heated to 70° C. as a solution in dioxane/water (3:1)for 2 h. Ethyl acetate was used as the extraction solvent during workup. The organic layer was dried, filtered, and concentrated in vacuo toyield a solid, which was further rinsed with diethyl ether anddichloromethane to deliver the desired compound, Compound I-364 (46 mg,72% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.47 (s, 1H), 9.10 (d, 1H), 8.40 (d,1H), 7.62 (s, 1H), 7.30-7.37 (m, 1H), 7.27 (d, 1H), 7.20-7.25 (m, 1H),7.11 (t, 1H), 6.84 (t, 1H), 5.91 (s, 2H), 4.90 (s, 2H), 3.98 (t, 2H),2.51-2.55 (m, 2H).

Compound I-365

The title compound was prepared following general procedure B, except(1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (as the HClsalt, 2 equiv.) was the amine reactant, 2.5 equivalents of triethylaminewas used, and contents were heated to 60° C. for 24 h, followed by 80°C. for 3 h. Ethyl acetate was used as the extraction solvent during workup. The crude material was purified via silica gel chromatographyutilizing a 0-100% ethyl acetate/hexanes gradient to yield a solid,which was further rinsed with diethyl ether and dichloromethane todeliver the desired compound, Compound I-365 (21 mg, 16% yield) as awhite solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.78 (d, 1H), 8.07-8.20 (m, 1H), 7.23-7.35(m, 2H), 7.08-7.15 (m, 1H), 7.04 (t, 1H), 6.94 (br. s., 1H), 6.79-6.87(m, 1H), 5.92-6.01 (m, 2H), 4.28-4.38 (m, 1H), 2.85-2.97 (m, 1H), 2.23(d, 1H), 1.72-1.98 (m, 4H), 1.48-1.71 (m, 2H).

Compound I-366

The title compound was prepared following general procedure B, exceptpiperidine-4-sulfonamide (2 equiv.) was the amine reactant, 2equivalents of triethylamine was used, and contents were heated to 75°C. as a solution in dioxane/water (3:1) for 2 h. The mixture was dilutedwith ethyl acetate and washed with 1N HCl solution. The insoluble solidswere collected via filtration and dried in vacuo to deliver the desiredcompound, Compound I-366 (64 mg, 48% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.10 (d, 1H), 8.35 (d, 1H), 7.60 (s,1H), 7.31-7.37 (m, 1H), 7.21-7.28 (m, 2H), 7.11 (t, 1H), 6.79-6.85 (m,3H), 5.91 (s, 2H), 4.66 (d, 2H), 3.24 (ddt, 1H), 3.16 (t, 2H), 2.13 (d,2H), 1.67 (qd, 2H).

Compound I-367

The title compound was synthesized in 3 steps:

Step 1: Synthesis of2-(1,3-dioxoisoindolin-2-yl)-N-methylethanesulfonamide

To a solution of 2-(1,3-dioxoisoindolin-2-yl)ethanesulfonyl chloride (1equiv.) in THF was added methylamine [2.0 M solution in THF] (2 equiv.).The mixture was stirred at 23° C. for 1 h. The mixture was concentratedto yield 2-(1,3-dioxoisoindolin-2-yl)-N-methylethanesulfonamide (0.98 g)as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 7.79-7.92 (m, 4H), 4.06-4.13 (m, 2H), 3.42(t, 2H), 2.74 (s, 3H).

Step 2: Synthesis of 2-amino-N-methylethanesulfonamide

To a suspension of2-(1,3-dioxoisoindolin-2-yl)-N-methylethanesulfonamide (1 equiv.) inethanol was added hydrazine monohydrate (1.5 equiv.). The mixture washeated to 75° C. for 2 h. The white precipitate formed was removed byfiltration. The filtrate was concentrated in vacuo to give2-amino-N-methylethanesulfonamide as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 3.20-3.24 (m, 2H), 3.08-3.14 (m, 2H), 2.71(s, 3H).

Step 3: Synthesis of Compound I-367

The title compound was prepared following general procedure B, except2-amino-N-methylethanesulfonamide (2 equiv.) was the amine reactant, 2equivalents of triethylamine was used, and contents were heated to 65°for 2 d. The mixture was diluted with ethyl acetate and washed withsaturated sodium bicarbonate solution. The organic layer was dried,filtered and evaporated to give a solid. The solid was purified viasilica gel chromatography (0 to 100% ethyl acetate in hexanes gradient)to deliver the desired compound, Compound I-367 (8.6 mg, 14% yield) as acream colored solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.76 (d, 1H), 8.10 (d, 1H), 7.49 (s, 1H),7.24-7.30 (m, 1H), 7.07-7.13 (m, 1H), 7.03 (t, 1H), 6.87-6.90 (m, 1H),6.81 (t, 1H), 5.96 (s, 2H), 4.01 (t, 2H), 3.42 (t, 2H), 2.68-2.70 (m,3H).

Compound I-368

The title compound was prepared following general procedure B, exceptN-methyltaurine (as the sodium salt, 2 equiv.) was the amine reactant, 2equivalents of triethylamine was used, and contents were heated to 65°C. as a solution in dioxane/water (3:1) for 24 h. Ethyl acetate was usedas solvent for work up. The organic layer was dried, filtered andevaporated to give a solid. The solid was collected by filtration anddried under vacuum to deliver the desired compound, Compound I-368 (31mg, 33% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.13 (d, 1H), 8.40 (d, 1H), 7.93 (br.s., 1H), 7.31-7.38 (m, 1H), 7.21-7.27 (m, 1H), 7.17 (s, 1H), 7.12 (t,1H), 6.88 (t, 1H), 5.96 (s, 2H), 3.94-4.02 (m, 2H), 3.38 (d, 3H),2.84-2.92 (m, 2H).

Compound I-369

The title compound was prepared following general procedure B, exceptcis-1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (2 equiv.)was the amine reactant, 2 equivalents of triethylamine was used, andcontents were heated to 65° C. as a solution in dioxane/water (3:1) for24 h. Ethyl acetate was used as solvent for work up. The crude materialwas purified via silica gel chromatography utilizing a 0-50% ethylacetate/hexanes gradient to deliver the desired compound, Compound I-369(7.0 mg, 10% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.07-9.10 (m, 1H), 8.22 (d, 1H), 7.70(d, 1H), 7.57 (s, 1H), 7.30-7.41 (m, 2H), 7.08-7.24 (m, 6H), 6.89 (t,1H), 5.91 (s, 2H), 2.99 (dt, 1H), 2.74-2.91 (m, 2H), 2.28-2.37 (m, 1H),1.94-2.01 (m, 1H).

Compound I-370

The title compound was prepared following general procedure B, except4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3 (2H)-one (as the HClsalt, 3.2 equiv.) was the amine reactant, 6 equivalents of triethylaminewas used, and contents were heated to 65° C. as a solution indioxane/water (1:1) for 24 h. The mixture was diluted with ethyl acetateand extracted with 1H HCl solution. The aqueous layer was basified withsaturated sodium bicarbonate solution and extracted with ethyl acetate.The combined organic layers were dried, filtered, and evaporated todeliver the desired compound, Compound I-370 (83 mg, 65% yield) as alight brown solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.38 (d, 1H), 8.08-8.21 (m, 1H), 7.22 (s,1H), 7.07-7.13 (m, 1H), 6.91 (t, 1H), 6.85 (t, 1H), 6.73-6.78 (m, 1H),6.52 (d, 1H), 5.85 (s, 2H), 4.69 (s, 2H), 3.83-3.91 (m, 2H), 2.52 (t,2H).

Compound I-371

The title compound was prepared following general procedure B, exceptcis-1-amino-2,3-dihydro-1H-indene-2-carboxylic acid (2 equiv.) was theamine reactant, 2 equivalents of triethylamine was used, and contentswere heated to 80° C. as a solution in dioxane/water (3:1) for 24 h. Themixture was diluted with ethyl acetate and washed with 1H HCl solution.The organic layer was dried, filtered, and concentrated in vacuo. Theresulting solid was rinsed with minimal amounts of methanol to deliverthe desired compound, Compound I-371 (11 mg, 16% yield) as a whitesolid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.10 (d, 1H) 8.25 (d, 1H) 7.63 (s, 1H)7.29-7.39 (m, 3H) 7.20-7.28 (m, 3H) 7.09-7.19 (m, 2H) 6.88 (t, 1H)6.22-6.29 (m, 1H) 5.87-5.97 (m, 2H) 3.67 (q, 1H) 3.52 (dd, 1H) 3.06 (dd,1H).

Compound I-372

The title compound was synthesized in 3 steps:

Step 1: Synthesis of tert-butylmethyl(2-oxo-2-(phenylsulfonamido)ethyl)carbamate

To a suspension of2-(((tert-butoxycarbonyl)amino)methyl)thiazole-4-carboxylic acid (1equiv.) and methyl iodide (10 equiv.) in THF at 0° C. was added sodiumhydride [60 wt % dispersion on mineral oil] (10 equiv.). The mixture wasstirred at 23° C. for 24 h. The mixture was diluted in ethyl acetate andwashed with 1N HCl solution. The organic layer was dried, filtered andevaporated to give an oil, which was further purified via silica gelchromatography (0 to 50% ethyl acetate/hexanes gradient) to give2-(((tert-butoxycarbonyl)(methyl)amino)methyl)thiazole-4-carboxylic acid(217 mg, 82% yield) as a red solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.26-8.34 (m, 1H), 4.76 (d, 2H), 3.00 (d,3H), 1.51 (br. s, 9H).

Step 2: Synthesis of ethyl 2-((methylamino)methyl)thiazole-4-carboxylatehydrochloride

A mixture of2-(((tert-butoxycarbonyl)(methyl)amino)methyl)thiazole-4-carboxylic acid(1 equiv.) and a solution of HCl [1.3 M in ethanol] (10 equiv.) wasstirred at 23° C. for 24 h. The mixture was concentrated to deliverethyl 2-((methylamino)methyl)thiazole-4-carboxylate (as the HCl salt,222 mg) as a yellow solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.46 (s, 1H), 4.63 (s, 2H), 4.27-4.37 (m,2H), 2.80 (s, 3H), 1.28-1.35 (m, 3H).

Step 3: Synthesis of Compound I-372

The title compound was prepared following general procedure B, exceptethyl 2-((methylamino)methyl)thiazole-4-carboxylate (as the HCl salt, 2equiv.) was the amine reactant, 6 equivalents of triethylamine was used,and contents were heated to 80° C. as a solution in dioxane/water (4:1)for 24 h. The mixture was diluted in ethyl acetate and washed withsaturated solution of sodium bicarbonate. The organic layer was dried,filtered and evaporated to give a solid, which was purified via silicagel chromatography (0 to 100% ethyl acetate in hexanes gradient) todeliver the desired compound, Compound I-372 (78 mg, 77% yield) as alight yellow gum.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.45 (d, 1H), 8.26 (d, 1H), 8.12 (s, 1H),7.28 (s, 1H), 7.17-7.23 (m, 1H), 6.94-7.06 (m, 2H), 6.86-6.92 (m, 1H),6.58 (d, 1H), 5.97 (s, 2H), 5.22 (s, 2H), 4.44 (q, 2H), 3.42 (d, 3H),1.42 (t, 3H).

Compound I-373

A mixture of Compound I-372 (1 equiv.) and lithium hydroxide (10 equiv.)in a THF/water/methanol (1:1:1) mix was stirred at 23° C. for 24 h. Themixture was concentrated in vacuo. The resulting solution was acidifiedto pH 1. The precipitate formed was collected by filtration and dried invacuo to deliver the desired compound, Compound I-373 (38 mg, 67% yield)as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.05 (s, 1H), 9.09 (d, 1H), 8.36 (t,2H), 7.57 (s, 1H), 7.30-7.37 (m, 1H), 7.18-7.26 (m, 2H), 7.11 (t, 1H),6.89 (t, 1H), 5.89 (s, 2H), 5.17 (s, 2H), 3.32-3.39 (m, 3H).

Compound I-374

A suspension of Compound I-368 (1 equiv.) in thionyl chloride (50equiv.) was heated to reflux for 24 h. The mixture was cooled andconcentrated in vacuo to give the intermediate sulfonyl chloride2-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)(methyl)amino)-ethanesulfonyl chloride (169 mg) as a yellow solid. This materialwas then treated with ammonia [0.05 M solution in 1,4-dioxane] (5equiv.) and the mixture was allowed to stir at 23° C. for 24 h. Thereaction was diluted in ethyl acetate and washed with saturated solutionof sodium bicarbonate. The organic layer was dried, filtered andevaporated to give an oil. The oil was purified via silica gelchromatography (0 to 30% methanol in dichloromethane gradient) andrecrystallized from a methanol:dichloromethane mixture to deliver thedesired compound, Compound I-374 (13 mg, 8% yield) as a light yellowsolid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.10 (d, 1H) 8.28 (d, 1H) 7.58 (s, 1H)7.33 (d, 1H) 7.19-7.25 (m, 1H) 7.14 (d, 1H) 7.08-7.13 (m, 2H) 5.89 (s,2H) 4.00-4.06 (m, 2H) 3.36-3.41 (m, 2H) 3.28 (d, 3H).

Compound I-375

The title compound was prepared in 3 steps:

Step 1: Synthesis of2-(((tert-butoxycarbonyl)(methyl)amino)methyl)oxazole-4-carboxylic acid

To a cold suspension of2-(((tert-butoxycarbonyl)amino)methyl)oxazole-4-carboxylic acid (1equiv.) and iodomethane (10 equiv.) in THF at 0° C., was added sodiumhydride [60 wt % dispersion on mineral oil] (10 equiv.). The mixture wasallowed to warm to 23° C. and stirred for 24 h. The mixture was dilutedin ethyl acetate and washed with 1N HCl solution. The organic layer wasdried, filtered and evaporated to give an oil. The oil was purified bycolumn chromatography (0 to 100% ethyl acetate in hexanes gradient) toyield 2-(((tert-butoxycarbonyl)(methyl)amino)methyl)oxazole-4-carboxylicacid (215 mg, 81% yield) as a yellow oil.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.27 (s, 1H), 4.52-4.69 (m, 2H), 2.93 (d,3H), 1.37-1.53 (m, 9H).

Step 2: Synthesis of 2-((methylamino)methyl)oxazole-4-carboxylic acid,TFA salt

A mixture of2-(((tert-butoxycarbonyl)(methyl)amino)methyl)oxazole-4-carboxylic acid(1 equiv) and TFA (10 equiv.) in DCM was stirred at 23° C. for 1 h. Themixture was concentrated to yield2-((methylamino)methyl)oxazole-4-carboxylic acid, TFA salt (237 mg) as aclear oil.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.62-8.64 (m, 1H), 4.49 (s, 2H), 2.86 (s,3H).

Step 3: Synthesis of Compound I-375

The title compound was prepared following general procedure B, except2-((methylamino)methyl)oxazole-4-carboxylic acid (as the TFA salt, 4equiv.) was the amine reactant, 8 equivalents of triethylamine was used,and contents were heated to 80° C. as a solution in dioxane/water (4:1)for 24 h. Ethyl acetate was used as solvent during work up. The crudeoil obtained after work up was treated with diethyl ether and theresulting precipitated solid was collected by filtration and dried invacuo to deliver the desired compound, Compound I-375 (68% yield) as awhite solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.10 (d, 1H), 8.73 (s, 1H), 8.36 (d,1H), 7.50 (s, 1H), 7.28-7.36 (m, 1H), 7.16-7.26 (m, 2H), 7.10 (t, 1H),6.85 (t, 1H), 5.88 (s, 2H), 5.07 (s, 2H), 3.35-3.40 (m, 3H).

Compound I-376

The title compound was synthesized in 2 steps:

Step 1: Synthesis of1-methyl-2-((methylamino)methyl)-1H-imidazole-4-carboxylic acidhydrochloride

To a suspension of2-(((tert-butoxycarbonyl)amino)methyl)-1H-imidazole-4-carboxylic acid (1equiv.) and methyl idodide (10 equiv.) in THF at 0° C., was added sodiumhydride [60 wt % dispersion on mineral oil] (10 equiv.). The mixture wasstirred at 23° C. for 24 h. The mixture was treated with a solution ofHCl [4.0 M solution in 1,4-dioxane]. The mixture was concentrated invacuo and the resulting solid was suspended in diethyl ether. Theprecipitate was collected by filtration and dried in vacuo to give1-methyl-2-((methylamino)methyl)-1H-imidazole-4-carboxylic acidhydrochloride (80 mg, 38% yield) as a yellow solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.34 (br. s., 2H), 7.91 (s, 1H), 4.29(t, 2H), 3.71 (s, 3H), 2.64 (t, 3H).

Step 2: Synthesis of Compound I-376

The title compound was prepared following general procedure B, except1-methyl-2-((methylamino)methyl)-1H-imidazole-4-carboxylic acid (as theHCl salt, 3 equiv.) was the amine reactant, 4 equivalents oftriethylamine was used, and contents were heated to 80° C. as a solutionin dioxane/water (4:1) for 24 h. The mixture was cooled to 23° C.,diluted in ethyl acetate, and was washed with 1N HCl solution. Theprecipitate formed was collected by filtration and dried in vacuo todeliver the desired compound, Compound I-376 (26 mg, 37% yield) as awhite solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.10 (d, 1H), 8.39 (d, 1H), 8.11 (br.s., 1H), 7.56 (s, 1H), 7.28-7.39 (m, 1H), 7.18-7.26 (m, 2H), 7.07-7.14(m, 1H), 6.82 (t, 1H), 5.91 (s, 2H), 5.08 (s, 2H), 3.85 (s, 3H), 3.41(d, 3H).

Compound I-377

The title compound was prepared following general procedure B, except3-(2-aminoethyl)benzoic acid was the amine reactant, 4 equivalents oftriethylamine was used, and contents were heated to 90° C. as a solutionin dioxane/water (3:1) for 24 h. Ethyl acetate was used as solventduring work up. The crude material was purified via silica gelchromatography, utilizing a 0-80% ethyl acetate/hexanes gradient todeliver the desired compound, Compound I-377 (25 mg, 31% yield) as awhite solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.44 (d, 1H), 8.17 (d, 1H), 8.04 (s, 1H),7.98 (d, 1H), 7.50 (d, 1H), 7.40-7.45 (m, 1H), 7.37 (s, 1H), 7.14-7.21(m, 1H), 7.00 (t, 1H), 6.92-6.97 (m, 1H), 6.85-6.92 (m, 1H), 6.64 (d,1H), 5.99 (s, 2H), 5.24-5.31 (m, 1H), 3.90-3.97 (m, 2H), 3.08 (t, 2H).

Compound I-378

The title compound was prepared following general procedure B, except5-hydroxy-1,2,3,6-tetrahydropyridine-4-carboxylate (as the TFA salt, 1equiv.) was the amine reactant, 3 equivalents of triethylamine was used,and contents were heated to 70° C. as a solution in dioxane/water (3:1)for 24 h. Ethyl acetate was used as solvent during work up. The crudematerial was purified via silica gel chromatography, utilizing a 0-30%ethyl acetate/hexanes gradient to deliver the desired compound, CompoundI-378 (68 mg, 15% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 12.17 (s, 1H), 8.46 (d, 1H), 8.23 (d, 1H),7.31 (s, 1H), 7.16-7.22 (m, 1H), 7.02 (t, 1H), 6.96 (t, 1H), 6.84 (t,1H), 6.62 (d, 1H), 5.98 (s, 2H), 4.47-4.50 (m, 2H), 4.26 (q, 2H), 3.94(t, 2H), 2.51 (t, 2H), 1.33 (t, 3H).

Compound I-379

The title compound was prepared following general procedure B, except(1SR,2SR,3RS,4RS)-3-aminobicyclo[2.2.1]heptane-2-carboxylic acid (as theHCl salt, racemic, 3 equiv.) was the amine reactant, 6 equivalents oftriethylamine was used, and contents were heated to 70° C. as a solutionin dioxane/water (3:1) for 24 h. The reaction mixture was cooled,diluted with ethyl acetate, and washed with water. The organic layer wasdried, filtered, and concentrated in vacuo. The crude material waspurified via silica gel chromatography, utilizing a 0-80% ethylacetate/hexanes gradient to deliver the desired compound, Compound I-379(47 mg, 36% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.76-8.79 (m, 1H), 8.07 (d, 1H), 7.42 (s,1H), 7.25-7.32 (m, 1H), 7.11 (ddd, 1H), 7.05 (td, 1H), 6.92 (d, 1H),6.83 (td, 1H), 5.97 (s, 2H), 4.58-4.66 (m, 1H), 3.13 (ddd, 1H), 2.83(br. s., 1H), 2.67 (br. s., 1H), 1.74 (d, 1H), 1.65-1.71 (m, 1H),1.58-1.64 (m, 1H), 1.49-1.57 (m, 2H), 1.41-1.49 (m, 1H).

Compound I-380

The title compound was prepared following general procedure B, except(1S,3R)-3-aminocyclohexanecarboxylic acid (98% ee, 4 equiv.) was theamine reactant, 4 equivalents of triethylamine was used, and contentswere heated to 80° C. as a solution in dioxane/water (3:1) for 24 h.Ethyl acetate was used as solvent during work up. The crude material waspurified via silica gel chromatography, utilizing a 0-10%methanol/dichloromethane gradient to deliver the desired compound,Compound I-380 (70 mg, 55% yield) as a yellow solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.81 (d, 1H), 8.18 (d, 1H), 7.59 (s, 1H),7.29 (q, 1H), 7.07-7.14 (m, 1H), 7.05 (t, 1H), 6.98 (d, 1H), 6.92 (t,1H), 6.00 (s, 2H), 4.46 (t, 1H), 2.59 (t, 1H), 2.31 (d, 1H), 2.04 (d,2H), 1.95 (d, 1H), 1.51-1.65 (m, 2H), 1.35-1.51 (m, 2H).

Compound I-381

The title compound was synthesized in 3 steps:

Step 1: Synthesis of2-(1,3-dioxoisoindolin-2-yl)-N-(2,2,2-trifluoroethyl) ethanesulfonamide

A mixture of 2-[2-(Chlorosulfonyl)ethyl]benzo[c]azoline-1,3-dione (1equiv.), 2,2,2-trifluoroethylamine hydrochloride (3 equiv.) andtriethylamine (6 equiv.) in dichloromethane was stirred at 23° C. for 24h. The mixture was diluted in dichloromethane and washed with 1N HClsolution. The organic layer was dried, filtered and evaporated to give awhite solid The solid was purified via silica gel chromatography (0 to100% ethyl acetate in hexanes) to give2-(1,3-dioxoisoindolin-2-yl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(370 mg, 30% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.84-7.92 (m, 4H), 4.05-4.09 (m, 2H),3.97-4.01 (m, 2H), 3.32 (s, 2H).

Step 2: Synthesis of 2-amino-N-(2,2,2-trifluoroethyl)ethanesulfonamide

A mixture of2-(1,3-dioxoisoindolin-2-yl)-N-(2,2,2-trifluoroethyl)ethanesulfonamide(1 equiv.) and hydrazine monohydrate (1 equiv.) in ethanol was stirredat 80° C. for 24 h. The mixture was cooled to 23° C. and concentrated invacuo. The resulting residue was treated with a minimal amount ofmethanol. The precipitate was collected by filtration and dried in vacuoto give a white solid containing2-amino-N-(2,2,2-trifluoroethyl)ethanesulfonamide (136 mg). The materialwas used in the next reaction without further purification.

Step 3: Synthesis of Compound I-381

The title compound was prepared following general procedure B, except2-amino-N-(2,2,2-trifluoroethyl)ethanesulfonamide (1 equiv.) was theamine reactant, 3 equivalents of triethylamine was used, and contentswere heated to 80° C. as a solution in dioxane/water (3:1) for 24 h. Themixture was cooled, diluted in ethyl acetate, and washed with water. Theorganic layer was dried, filtered and evaporated to give an oil. The oilwas purified via silica gel chromatography (0 to 70% ethyl acetate inhexanes gradient) to deliver the desired compound, Compound I-xxx (28mg, 14% yield over step 2 and 3) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.10 (d, 1H), 8.25 (d, 2H), 7.55 (s,1H), 7.30-7.37 (m, 1H), 7.19-7.26 (m, 1H), 7.15 (d, 1H), 7.10 (t, 1H),6.82 (t, 1H), 5.89 (s, 2H), 3.87-3.82 (m, 4H), 3.45 (t, 2H).

Compound I-382

The title compound was synthesized in 2 steps:

Step 1: Synthesis of 2-hydroxy-N-2-dimethyl-3-(methylamino)propanamide

In a sealed vial, a mixture of methyl 2-methylglycidate (1 equiv.) andmethylamine [33 wt % in THF] (10 equiv.) was heated to 80° C. for 24 h.The mixture was concentrated under vacuum to give2-hydroxy-N-2-dimethyl-3-(methylamino)propanamide (1.7 g, 100% yield) asa clear oil.

¹H NMR (500 MHz, CDCl₃) δ ppm 3.67-3.76 (m, 1H), 3.22-3.29 (m, 1H),2.79-2.82 (m, 3H), 2.40-2.43 (m, 3H), 1.31-1.33 (m, 3H).

Step 2: Synthesis of Compound I-382

The title compound was prepared following general procedure B, except2-hydroxy-N-2-dimethyl-3-(methylamino)propanamide (4 equiv.) was theamine reactant, 4 equivalents of triethylamine was used, and contentswere heated to 80° C. as a solution in dioxane/water (3:1) for 4 h.Ethyl acetate was used as solvent during work up. The resulting solidwas treated with a minimal amount of methanol and diethyl ether,collected by filtration, and dried in vacuo to deliver the desiredcompound, Compound I-382 (67 mg, 52% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.09-9.12 (m, 1H), 8.23 (d, 1H), 7.87(q, 1H), 7.54 (s, 1H), 7.30-7.37 (m, 1H), 7.18-7.26 (m, 1H), 7.11 (td,1H), 6.88 (t, 1H), 5.86-5.92 (m, 2H), 4.12 (d, 1H), 3.68 (d, 1H), 3.22(s, 3H), 2.55 (d, 3H), 1.27 (s, 3H).

Compound I-383

The title compound was synthesized in 5 steps:

Step 1: Synthesis of benzyl (3-hydroxy-2,2-dimethylpropyl)carbamate

To a cold mixture of 3-amino-2,2-dimethyl-1-propanol (1 equiv.) andtriethylamine (1 equiv.) in dichloromethane was added benzylchloroformate (1 equiv.). The mixture was stirred at 23° C. for 30 min,then diluted in dichloromethane and washed with 1N HCl solution. Theorganic layer was dried, filtered, and evaporated to give benzyl(3-hydroxy-2,2-dimethylpropyl)carbamate (1.9 g, 86% yield) as a whitesolid.

¹H NMR (500 MHz, CDCl₃) δ ppm 7.34-7.45 (m, 5H), 5.14 (s, 2H), 3.25 (d,2H), 3.08 (d, 2H), 0.89 (s, 6H).

Step 2: Synthesis of3-(((benzyloxy)carbonyl)amino)-2,2-dimethylpropanoic acid

To a suspension of benzyl (3-hydroxy-2,2-dimethylpropyl)carbamate (1equiv.) in CCl₄, water, and acetonitrile (1:1:1 mixture) were addedsodium periodate (3 equiv.) and ruthenium (III) chloride (0.05 equiv.).The mixture was stirred at 23° C. for 24 h. To this mixture, additionalamounts of sodium periodate (3 equiv.) and ruthenium(III) chloride (0.05equiv.) were added, and contents stirred at 23° C. for 3 days. Themixture was diluted with water and extracted with ethyl acetate. Theorganic layer was extracted with saturated solution of sodium carbonate,then the aqueous layer was acidified to pH 1 and extracted with ethylacetate. The organic layer was dried, filtered and evaporated to give anoil. The oil was purified via silica gel chromatography (0 to 100% ethylacetate in hexanes gradient) to give3-(((benzyloxy)carbonyl)amino)-2,2-dimethylpropanoic acid (943 mg, 45%yield) as a red colored oil.

¹H NMR (500 MHz, CDCl₃) δ ppm 7.35-7.42 (m, 5H), 5.12 (s, 2H), 3.35 (d,2H), 1.23-1.28 (m, 6H).

Step 3: Synthesis of3-(((benzyloxy)carbonyl)(methyl)amino)-2,2-dimethylpropanoic acid

To a cold solution of3-(((benzyloxy)carbonyl)amino)-2,2-dimethylpropanoic acid (1 equiv.) inTHF was added sodium hydride [60 wt % dispersion in mineral oil] (10equiv.). The mixture was stirred at 0° C. for 30 min. To this mixture,was added methyl iodide (10 equiv.). The mixture was allowed to warm to23° C. and stirred for 24 h. The mixture was poured over ice andacidified to pH 1. The mixture was extracted with diethyl ether, and theorganic layer was dried, filtered, and evaporated to give an oil. Theoil was purified via silica gel chromatography (0 to 80% ethyl acetatein hexanes gradient) to give3-(((benzyloxy)carbonyl)(methyl)amino)-2,2-dimethylpropanoic acid (686mg, 69% yield) as a clear oil.

¹H NMR (500 MHz, CDCl₃) δ ppm 7.36-7.39 (m, 4H), 7.32-7.35 (m, 1H), 5.13(s, 2H), 3.53-3.60 (m, 2H), 2.96 (br. s., 3H), 1.18-1.26 (m, 6H).

Step 4: Synthesis of 2,2-dimethyl-3-(methylamino)propanoic acidhydrochloride

A solution containing3-(((benzyloxy)carbonyl)(methyl)amino)-2,2-dimethylpropanoic acid (1equiv.) in methanol was hydrogenated using the H-cube (0.7 ml/min,catalyst: 10% Pd/C, 70° C.). The resulting mixture was treated with asolution of HCl [1.25 M in ethanol] and concentrated under vacuum togive 2,2-dimethyl-3-(methylamino)propanoic acid hydrochloride (569 mg,100% yield) as a clear oil.

¹H NMR (500 MHz, CD₃OD) δ ppm 3.09 (s, 2H), 2.69-2.74 (m, 3H), 1.25-1.31(m, 6H).

Step 5: Synthesis of Compound I-383

The title compound was prepared following general procedure B, except2,2-dimethyl-3-(methylamino)propanoic acid (as the HCl salt, 4 equiv.)was the amine reactant, 8 equivalents of triethylamine was used, andcontents were heated to 80° C. as a solution in dioxane/water (3:1) for24 h. Ethyl acetate was used as solvent during work up. The crudematerial was purified via silica gel chromatography (0 to 60% ethylacetate in hexanes gradient) to deliver the desired compound, CompoundI-383 (38 mg, 30% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.51 (br. s., 1H), 9.10 (d, 1H), 8.25(d, 1H), 7.49 (s, 1H), 7.30-7.37 (m, 1H), 7.18-7.25 (m, 2H), 7.11 (td,1H), 6.92 (t, 1H), 5.88 (s, 2H), 3.96 (s, 2H), 3.33 (s, 3H), 1.13 (s,6H).

Compound I-384

The title compound was prepared following general procedure B, except(1RS,2SR,3RS,4SR)-3-amino-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid(i.e. racemic, 4 equiv.) was the amine reactant, 4 equivalents oftriethylamine was used, and contents were heated to 80° C. as a solutionin dioxane/water (3:1) for 24 h. Ethyl acetate was used as solventduring work up. The resulting solid was rinsed with methanol and diethylether, collected by filtration, and dried in vacuo to deliver thedesired compound, Compound I-384 (43 mg, 33% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.40 (br. s., 1H), 9.10 (d, 1H), 8.23(d, 1H), 7.54 (s, 1H), 7.30-7.36 (m, 1H), 7.20-7.25 (m, 2H), 7.09-7.13(m, 1H), 6.94 (d, 1H), 6.83-6.87 (m, 1H), 5.89 (s, 2H), 4.86 (t, 1H),4.72 (d, 1H), 4.47 (d, 1H), 3.10 (d, 1H), 1.53-1.68 (m, 4H).

Compound I-436

The title compound was prepared following general procedure B, except2-aminoethanesulfonamide was the amine reactant, 3 equivalents oftriethylamine was used, and contents were heated to 65° C. for 24 h as asolution in dioxane. The mixture was diluted in ethyl acetate and washedwith saturated ammonium chloride solution. The organic layer was dried,filtered and evaporated to give a solid. The solid was purified viasilica gel chromatography (0-100% ethyl acetate in hexanes gradient) todeliver the desired compound, Compound I-436 (26 mg, 42% yield) as awhite solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.77 (d, 1H), 8.12 (d, 1H), 7.50 (s, 1H),7.25-7.32 (m, 1H), 7.03-7.14 (m, 2H), 6.90 (d, 1H), 6.82-6.88 (m, 1H),5.98 (s, 2H), 4.07-4.15 (m, 5H), 3.47 (t, 2H).

Compound I-385

To a solution of acetic acid (10 equiv.) in DMF was added CDI (10equiv.). The mixture was stirred at 45° C. for 30 min. To this mixturewas added Compound I-436 and DBU (10 equiv.). The mixture was stirred at23° C. for 3 d. The mixture was diluted in ethyl acetate and washed with1N HCl solution. The organic layer was dried, filtered and evaporated togive an oil. The oil was purified by silica gel chromatography (0 to 10%methanol in dichloromethane gradient) to deliver the desired compound,Compound I-385 (8.2 mg, 25% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.10 (d, 1H), 8.24 (d, 1H), 7.55 (s,1H), 7.30-7.37 (m, 1H), 7.17-7.26 (m, 2H), 7.11 (t, 1H), 6.86 (t, 1H),5.90 (s, 2H), 3.75-3.87 (m, 4H), 1.99 (s, 3H).

Compound I-387

The title compound was synthesized in 3 steps:

Step 1: Synthesis of tert-butyl(1-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)azetidin-3-yl)carbamate(Compound I-21)

The intermediate was prepared following general procedure B, except3-(tert-butoxycarbonylamino)azetidine was the amine reactant, 3equivalents of triethylamine was used, and contents were heated to 80°C. as a solution in dioxane/water (3:1) for 24 h. Ethyl acetate was usedas solvent during work up. The organic layer was dried, filtered, andconcentrated in vacuo to deliver the desired intermediate, tert-butyl(1-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)azetidin-3-yl)carbamate(480 mg, 100% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.09 (d, 1H), 8.28 (d, 1H), 7.65 (d,1H), 7.53 (s, 1H), 7.29-7.35 (m, 1H), 7.20-7.25 (m, 2H), 7.08-7.12 (m,1H), 6.81 (t, 1H), 5.91 (s, 2H), 4.49 (br. s., 3H), 4.12 (br. s., 2H),1.40 (s, 9H).

Step 2: Synthesis of1-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)azetidin-3-amine(Compound I-40)

A mixture of tert-butyl(1-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)azetidin-3-yl)carbamate(1 equiv.) and TFA (10 equiv.) in dichloromethane was stirred at 23° C.for 24 h. The mixture was concentrated in vacuo. The resulting oil wastreated with saturated solution of sodium bicarbonate and extracted withethyl acetate. The precipitate formed was collected and dried in vacuo.The organic layer was also dried, filtered, and evaporated to give1-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)azetidin-3-amine(116 mg (combined), 36% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.81-8.83 (m, 1H) 8.32 (d, 1H) 7.52-7.55(m, 1H) 7.27-7.34 (m, 1H) 7.02-7.14 (m, 2H) 6.89-6.95 (m, 2H) 6.00 (s,2H) 4.84-4.88 (m, 2H) 4.55 (d, 2H) 4.35-4.42 (m, 1H).

Step 3: Synthesis of Compound I-387

To a white suspension containing1-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)azetidin-3-amine(1 equiv.) and pyridine (10 equiv.) in THF was added trifluoromethanesulfonic anhydride (2 equiv.). The mixture was stirred at 23° C. for 30min. The mixture was diluted with ethyl acetate and washed with 1 N HClsolution. The organic layer was dried, filtered and evaporated to givean oil. The oil was purified via silica gel chromatography (0 to 80%ethyl acetate in hexanes gradient) to deliver the desired compound,Compound I-387 (61 mg, 48% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.10 (d, 1H), 9.08 (d, 1H), 8.30 (d,1H), 7.52 (s, 1H), 7.30-7.36 (m, 1H), 7.16-7.27 (m, 2H), 7.10 (t, 1H),6.81 (t, 1H), 5.90 (s, 2H), 4.71-4.83 (m, 1H), 4.52-4.63 (m, 2H), 4.27(dd, 2H).

Compound I-388

To a cold suspension of1-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)azetidin-3-amine(generated in step 2 of procedure toward Compound I-387 1 equiv.) andpyridine (4 equiv.) in dichloromethane at −78° C. was addedtrifluoromethane sulfonic anhydride (2 equiv.). The mixture was stirredat −78° C. for 2 h. Then, it was removed from the dry ice-acetone bathand warmed to 23° C. The stirring was continued at 23° C. for anadditional 1 h. The mixture was quenched with methanol, and concentratedin vacuo. The residue was dissolved in ethyl acetate and washed with 1NHCl solution. The organic layer was dried, filtered and evaporated togive an oil. The oil was purified via silica gel chromatography (0 to100% ethyl acetate in hexanes gradient), and the isolated material wasrecrystallized from a diethyl ether and methanol mixture to deliver thedesired compound, Compound I-388 (90 mg, 19% yield) as a light yellowsolid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.10 (d, 1H), 8.35 (br. s., 1H), 7.57(br. s., 1H), 7.31-7.37 (m, 1H), 7.19-7.28 (m, 2H), 7.11 (t, 1H), 6.82(t, 1H), 5.92 (s, 2H), 4.67 (br. s., 2H), 4.61 (br. s., 1H), 4.22 (br.s., 2H).

Compound I-389

The title compound was synthesized in 2 steps:

Step 1: Synthesis of 3-amino-2-hydroxy-2-methylpropanamide

A mixture of ammonia [7M in methanol] (20 equiv.) and methyl2-methylglycidate (1 equiv.) was stirred in a sealed vial at 80° C. for24 h. The mixture was concentrated in vacuo to give3-amino-2-hydroxy-2-methylpropanamide (731 mg, 100% yield) as a clearoil which turned into a white solid upon standing at 23° C.

¹H NMR (500 MHz, CD₃OD) δ ppm 2.90-2.96 (m, 1H) 2.60-2.66 (m, 1H)1.32-1.35 (m, 3H).

Step 2: Synthesis of Compound I-389

The title compound was prepared following general procedure B, except3-amino-2-hydroxy-2-methylpropanamide (4 equiv.) was the amine reactant,4 equivalents of triethylamine was used, and contents were heated to 80°C. as a solution in dioxane/water (3:1) for 24 h. The mixture wasdiluted in ethyl acetate and washed with water. The organic layer wasdried, filtered and evaporated to give a solid. The solid was purifiedvia silica gel chromatography (0 to 5% methanol in dichloromethanegradient) to deliver the desired compound, Compound I-389 (78 mg, 25%yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.23 (d, 1H), 7.50 (s, 1H), 7.30-7.35(m, 2H), 7.27 (t, 1H), 7.25-7.29 (m, 1H), 7.20-7.24 (m, 3H), 7.10 (td,1H), 6.86 (t, 1H), 5.94 (s, 1H), 5.89 (s, 2H), 3.75 (dd, 1H), 3.59 (dd,1H), 1.28 (s, 3H).

Compound I-390

The title compound was prepared following general procedure B, excepttert-butyl N-(2-aminoethyl)carbamate (4 equiv.) was the amine reactant,4 equivalents of triethylamine was used, and contents were heated to 85°C. as a solution in dioxane/water (3:1) for 3 h. Ethyl acetate was usedas solvent during work up. The organic layers were dried, filtered, andconcentrated in vacuo to deliver the desired compound, Compound I-390(200 mg, 75% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.13 (s, 1H), 8.30 (d, 1H), 7.71 (s,1H), 7.31-7.37 (m, 1H), 7.19-7.26 (m, 2H), 7.11 (t, 1H), 6.98 (t, 1H),6.86 (t, 1H), 5.92 (s, 2H), 3.50-3.59 (m, 3H), 3.25 (q, 2H), 1.31-1.37(m, 9H).

Compound I-391

A mixture of Compound I-390 (1 equiv.) and HCl [4.0 M in 1,4-dioxane](50 equiv.) was stirred at 23° C. for 24 h. The mixture was concentratedin vacuo to deliver the desired compound, Compound I-391 (as the HClsalt, 157 mg, 100% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.11 (s, 1H), 8.31 (br. s., 1H), 7.73(br. s., 1H), 7.26-7.38 (m, 2H), 7.21-7.26 (m, 1H), 7.11 (t, 1H), 6.83(t, 1H), 5.91 (s, 2H), 3.74 (br. s., 2H), 3.07-3.15 (m, 2H).

Compound I-392 A mixture containing Compound I-391 (1 equiv.), DBU (2.0equiv.), triethylamine (2 equiv.) andN-phenyl-bis(trifluoromethanesulfonimide) (1.2 equiv.) in acetonitrilewas stirred at 23° C. for 24 h. The mixture was concentrated in vacuo.The resulting residue was diluted in ethyl acetate and washed withwater. The organic layer was dried, filtered and evaporated to give anoil. The oil was purified by silica gel chromatography (0 to 100% ethylacetate in hexanes gradient). Recrystallization of the purified materialdelivered the desired compound, Compound I-392 (123 mg, 19% yield) as awhite solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.56 (s, 1H), 9.11 (d, 1H), 8.22 (d,1H), 7.87 (t, 1H), 7.51 (s, 1H), 7.30-7.35 (m, 1H), 7.20-7.24 (m, 1H),7.08-7.13 (m, 2H), 6.83-6.87 (m, 1H), 5.89 (s, 2H), 3.60 (q, 2H), 3.46(d, 2H).

Compound I-393

The title compound was synthesized in 3 steps:

Step 1: Synthesis of methyl 2-hydroxy-2-methyl-3-(methylamino)propanoate

A mixture of methanamine [2.0 M in THF] (1.3 equiv) and methyl2-methylglycidate (1 equiv.) in ethanol was heated to 80° C. for 24 h.The mixture was concentrated to give methyl2-hydroxy-2-methyl-3-(methylamino)propanoate (2.26 g) as a clear oil.The mixture was taken onto the next step without further purification.

Step 2: Synthesis of 2-hydroxy-2-methyl-3-(methylamino)propanamide

A mixture of methyl 2-hydroxy-2-methyl-3-(methylamino)propanoate (1equiv.) and ammonia [7.0 M in methanol] (5 equiv.) was heated to 85° C.in a sealed vial for 24 h. The mixture was concentrated to give2-hydroxy-2-methyl-3-(methylamino)propanamide as a thick oil. Thematerial was used in the next reaction without further purification.

Step 3: Synthesis of Compound I-393

The title compound was prepared following general procedure B, except2-hydroxy-2-methyl-3-(methylamino)propanamide (4 equiv.) was the aminereactant, 4 equivalents of triethylamine was used, and contents wereheated to 85° C. as a solution in dioxane/water (3:1) for 24 h. Themixture was cooled to 23° C. and the white precipitate formed wascollected by filtration, rinsed with diethyl ether and dried in vacuo todeliver the desired compound, Compound I-393 (45 mg, 11% yield over step3) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.09 (d, 1H), 8.21 (d, 1H), 7.52 (s,1H), 7.27-7.36 (m, 2H), 7.19-7.26 (m, 1H), 7.10 (t, 1H), 6.88 (t, 1H),5.88 (s, 2H), 4.11 (d, 1H), 3.72 (d, 1H), 3.26 (d, 3H), 1.25 (s, 3H).

Compound I-394

The title compound was synthesized in 3 steps:

Step 1: Synthesis of tert-butyl3-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)azetidine-1-carboxylate

The intermediate was prepared following general procedure B, excepttert-butyl 3-aminoazetidine-1-carboxylate (4 equiv.) was the aminereactant, 4 equivalents of triethylamine was used, and contents wereheated to 80° C. as a solution in dioxane/water (3:1) for 24 h. Ethylacetate was used as solvent during work up. The organic layer was dried,filtered and evaporated to give tert-butyl3-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)azetidine-1-carboxylate(505 mg, 100% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.10 (d, 1H), 8.45 (br. s., 1H), 8.36(d, 1H), 8.27 (d, 1H), 7.53-7.57 (m, 1H), 7.30-7.37 (m, 1H), 7.19-7.28(m, 1H), 7.11 (t, 1H), 6.83-6.91 (m, 1H), 5.90 (s, 2H), 4.81-4.90 (m,1H), 4.21 (br. s., 2H), 3.92 (dd, 2H), 1.36-1.41 (m, 9H).

Step 2: Synthesis ofN-(azetidin-3-yl)-5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-aminehydrochloride

A mixture of tert-butyl3-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)azetidine-1-carboxylate (1 equiv.) and hydrogenchloride [4.0 M in 1,4-dioxane] (10 equiv.) was stirred at 23° C. for 4h. The mixture was concentrated in vacuo to giveN-(azetidin-3-yl)-5-fluoro-2-(1-(2-fluorobenzyl)5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine (as the HCl salt,450 mg, 100% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.13-9.16 (m, 1H), 8.40-8.49 (m, 1H),7.62-7.70 (m, 1H), 7.32-7.39 (m, 1H), 7.28 (dd, 1H), 7.21-7.25 (m, 1H),7.12 (td, 1H), 6.89 (t, 1H), 5.93 (s, 2H), 4.95-5.02 (m, 1H), 4.26-4.35(m, 3H), 4.17-4.25 (m, 2H).

Step 3: Synthesis of Compound I-394

To a cold mixture ofN-(azetidin-3-yl)-5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-aminehydrochloride (1 equiv.), triethylamine (3 equiv.) and pyridine (245 μl,3 equiv.) in dichloromethane at −78° C. was addedtrifluoromethanesulfonic anhydride (4 equiv.). The mixture was stirredat −78° C. for 2 h before it was warmed up to 23° C. Then, the mixturewas treated with 1N HCl solution and extracted with ethyl acetate. Theorganic layer was dried, filtered, and evaporated to give an oil. Theoil was purified via silica gel chromatography (0 to 30% ethyl acetatein hexanes gradient) to deliver the desired compound, Compound I-394 (90mg, 16% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.83 (d, 1H), 8.32 (d, 1H), 7.62 (s, 1H),7.29-7.34 (m, 1H), 7.05-7.13 (m, 2H), 6.96-7.00 (m, 2H), 6.03 (s, 2H),4.98 (br. s., 2H), 4.74-4.83 (m, 1H), 4.53 (br. s., 2H).

Compound I-395

The title compound was prepared following general procedure B, except(1R,2S)-(+)-cis-1-amino-2-indanol (4 equiv.) was the amine reactant, 4equivalents of triethylamine was used, and contents were heated to 80°C. as a solution in dioxane/water (3:1) for 3 h. Ethyl acetate was usedas solvent during work up. The crude material was purified via silicagel chromatography utilizing a 0-50% ethyl acetate/hexanes gradient todeliver the desired compound, Compound I-395 (4 mg, 27% yield) as acream colored solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.07 (d, 1H), 8.28 (d, 1H), 7.55 (s,1H), 7.30-7.37 (m, 2H), 7.26-7.29 (m, 1H), 7.13-7.25 (m, 5H), 7.10 (td,1H), 6.80-6.87 (m, 1H), 5.89 (s, 2H), 5.75 (dd, 1H), 5.27 (d, 1H), 4.60(d, 1H), 3.15 (dd, 1H), 2.93 (dd, 1H).

Compound I-396

The title compound was prepared following general procedure B, except3-(trifluoromethyl)azetidin-3-ol (3 equiv.) was the amine reactant, 3equivalents of triethylamine was used, and contents were heated to 80°C. as a solution in dioxane/water (3:1) for 3 h. Ethyl acetate was usedas solvent during work up. The organic layer was dried, filtered, andconcentrated in vacuo to yield a solid, which was rinsed with minimalamounts of methanol and diethyl ether and dried in vacuo to deliver thedesired compound, Compound I-396 (57 mg, 45% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.09 (d, 1H), 8.37 (d, 1H), 7.57 (s,2H), 7.30-7.36 (m, 1H), 7.19-7.26 (m, 2H), 7.10 (td, 1H), 6.82 (t, 1H),5.91 (s, 2H), 4.52 (d, 2H), 4.30 (d, 2H).

Compound I-397

The title compound was prepared following general procedure B, except4-(aminomethyl)tetrahydro-2H-pyran-4-ol (3 equiv.) was the aminereactant, 3 equivalents of triethylamine was used, and contents wereheated to 80° C. as a solution in dioxane/water (3:1) for 24 h. Ethylacetate was used as solvent during work up. The organic layer was dried,filtered, and concentrated in vacuo to deliver the desired compound,Compound I-397 (30 mg, 24% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.80 (d, 1H), 8.20 (d, 1H), 7.57 (s, 1H),7.24-7.32 (m, 1H), 7.02-7.13 (m, 2H), 6.87-6.97 (m, 2H), 5.99 (s, 2H),3.74-3.80 (m, 6H), 1.76-1.85 (m, 2H), 1.59 (d, 2H).

Compound I-398

The title compound was prepared following general procedure B, except2-amino-4,4-difluorobutanoic acid (3 equiv.) was the amine reactant, 3equivalents of triethylamine was used, and contents were heated to 80°C. as a solution in dioxane/water (4:1) for 24 h. Ethyl acetate was usedas solvent during work up. The organic layer was dried, filtered, andconcentrated in vacuo to yield a solid, which was rinsed with minimalamounts of methanol and diethyl ether and dried in vacuo to deliver thedesired compound, Compound I-398 (123 mg, 52% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.10 (d, 1H), 8.29 (d, 1H), 8.12 (d,1H), 7.42 (s, 1H), 7.32 (d, 1H), 7.18-7.24 (m, 1H), 7.16 (d, 1H), 7.10(t, 1H), 6.85 (t, 1H), 6.09-6.37 (m, 2H), 5.87 (s, 2H), 4.85 (d, 1H),4.04 (s, 1H).

Compound I-399

To a suspension of Compound I-398 (1 equiv.) in THF was added lithiumaluminum hydride [1.0 M solution in THF] (3 equiv.). The mixture wasstirred at 23° C. for an additional 24 h. The mixture was quenched withwater, followed by 15% NaOH solution followed by water. The mixture wasdiluted with ethyl acetate and washed with 1N HCl solution. The organiclayer was dried, filtered, and evaporated to give an oil. The oil waspurified via silica gel chromatography (0 to 100% ethyl acetate inhexanes gradient) to deliver the desired compound, Compound I-399 (23mg, 12% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.75 (d, 1H), 8.08 (d, 1H), 7.43 (s, 1H),7.23-7.30 (m, 1H), 7.06-7.12 (m, 1H), 7.03 (t, 1H), 6.87-6.89 (m, 1H),6.81 (t, 1H), 6.05-6.21 (m, 1H), 5.93-5.98 (m, 2H), 4.71 (dq, 1H),3.63-3.75 (m, 2H), 2.18-2.35 (m, 2H).

Compound I-400

A mixture of 2,2-bis(trifluoromethyl)-2-hydroxyacetic acid (1.5 equiv.)and CDI (1.5 equiv.) in THF was heated to reflux for 2 h. To thismixture was added2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine(Intermediate previous described in patent application publicationWO2012/3405 A1) (1 equiv.) in one portion. The mixture was heated toreflux for 3 h. Then, it was cooled to 23° C., diluted in ethyl acetateand washed with 1N HCl solution. The organic layer was dried, filteredand evaporated to give an oil. The oil was purified by silica gelchromatography (0 to 80% ethyl acetate in hexanes gradient) to deliverthe desired compound, Compound I-400 (111 mg, 35% yield) as a whitesolid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.79-8.82 (m, 1H), 8.75-8.77 (m, 1H),8.07-8.10 (m, 1H), 7.54-7.56 (m, 1H), 7.22-7.31 (m, 1H), 6.99-7.12 (m,2H), 6.86-6.93 (m, 2H), 5.95-6.00 (m, 2H).

Compound I-401

The title compound was synthesized in 2 steps:

Step 1: Synthesis of(S)-4-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)-5-methoxy-5-oxopentanoicacid

The intermediate was prepared following general procedure B, exceptL-glutamate methyl ester (4 equiv.) was the amine reactant, 4equivalents of triethylamine was used, and contents were heated to 80°C. as a solution in dioxane/water (3:1) for 24 h. The mixture wasconcentrated under vacuum. The resulting solid was rinsed with diethylether and water, and collected by filtration and dried in vacuo to give(S)-4-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)-5-methoxy-5-oxopentanoic acid (274 mg, 69% yield)as a yellow solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.76-8.78 (m, 1H) 8.15 (d, 1H) 7.37 (s,1H) 7.23-7.31 (m, 2H) 6.99-7.13 (m, 2H) 6.84 (t, 1H) 5.94-5.99 (m, 2H)3.73 (s, 1H) 3.34 (s, 3H) 2.29-2.43 (m, 2H) 2.12-2.24 (m, 2H).

Step 2: Synthesis of Compound I-401

To a solution of(S)-4-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)-5-methoxy-5-oxopentanoicacid (1 equiv.) in THF were added oxalyl chloride (1.5 equiv.) and adrop of DMF. The mixture was stirred at 23° C. for 30 min. Then, it washeated to reflux for 30 min. The mixture was cooled to 23° C., dilutedwith ethyl acetate, and washed with 1N HCl solution. The organic layerwas dried, filtered, and evaporated to give an oil. The oil was purifiedby silica gel chromatography (0 to 50% ethyl acetate in hexanesgradient) to deliver the desired compound, Compound I-401 (81 mg, 33%yield) as a light yellow solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.76-8.78 (m, 1H), 8.71-8.74 (m, 1H),7.32-7.35 (m, 1H), 7.23-7.30 (m, 1H), 7.06-7.12 (m, 1H), 7.00-7.05 (m,1H), 6.81-6.90 (m, 2H), 5.94 (s, 2H), 5.10 (dd, 1H), 3.75 (s, 3H),2.59-2.80 (m, 3H), 2.23-2.33 (m, 1H).

Compound I-403

The title compound was prepared following general procedure B, except2-amino-3,3,3-trifluoropropanoic acid (3 equiv.) was the amine reactant,3 equivalents of triethylamine was used, and contents were heated to 70°C. for 24 h as a solution in dioxane/water (3:1). Ethyl acetate was usedas solvent during work up. The organic layer was dried, filtered, andconcentrated in vacuo to yield a solid, which was rinsed with minimalamounts of methanol and diethyl ether and dried in vacuo to deliver thedesired compound, Compound I-403 (71 mg, 17% yield) as a yellow solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.76 (d, 1H), 8.27 (d, 1H), 7.48-7.51 (m,1H), 7.24-7.31 (m, 1H), 7.07-7.13 (m, 1H), 7.00-7.06 (m, 1H), 6.92 (d,1H), 6.80 (t, 1H), 6.10-6.16 (m, 1H), 5.98 (s, 2H).

Compound I-404

To a suspension of Compound I-403 (1 equiv.) in THF was added lithiumaluminum hydride [1.0 M solution in THF] (2 equiv.). The mixture wasstirred at 23° C. for 1 h. The mixture was quenched with water, followedby 15% NaOH solution followed by water. The mixture was diluted withethyl acetate and washed with 1N HCl solution. The organic layer wasdried, filtered, and evaporated to give a solid. The solid was purifiedvia silica gel chromatography (0 to 50% ethyl acetate in hexanesgradient) to deliver the desired compound, Compound I-404 (19 mg, 12%yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.75-8.77 (m, 1H), 8.21 (d, 1H), 7.46-7.48(m, 1H), 7.24-7.31 (m, 1H), 7.06-7.14 (m, 1H), 7.03 (t, 1H), 6.89-6.94(m, 1H), 6.79 (t, 1H), 5.97 (d, 2H), 5.47-5.54 (m, 1H), 3.87-4.01 (m,2H).

Compound I-405

The title compound was synthesized in 3 steps:

Step 1: Synthesis of 2-(trifluoromethyl)oxirane-2-carboxamide

To a solution of 2-(bromomethyl)-3,3,3-trifluoro-2-hydroxypropanamide (1equiv.) in acetone was added potassium carbonate (2 equiv.). The mixturewas heated to reflux for 2 h. The mixture was concentrated under invacuo. The resulting residue was diluted with water and extracted withethyl acetate. The organic layer was dried, filtered and evaporated togive 2-(trifluoromethyl)oxirane-2-carboxamide (1.44 g 76% yield) as ayellow gum.

¹H NMR (500 MHz, CD₃OD) δ ppm 3.17 (dd, 2H).

Step 2: Synthesis of2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropanamide

A mixture of ammonia [7M in methanol] (10 equiv.) and2-(trifluoromethyl)oxirane-2-carboxamide (1 equiv.) was stirred in asealed vial at 80° C. for 24 h. The mixture was concentrated in vacuo togive 2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropanamide (1.3 g, 84%yield) as a brown gum.

¹H NMR (500 MHz, DMSO-d₆) δ 3.01-3.11 (m, 1H), 2.84 (d, 1H).

Step 3: Synthesis of Compound I-405

The title compound was prepared following general procedure B, except2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropanamide (4 equiv.) was theamine reactant, 4 equivalents of triethylamine was used, and contentswere heated to 90° C. for 24 h as a solution in dioxane/water (3:1). Themixture was diluted in ethyl acetate and washed with water. The organiclayer was dried, filtered and evaporated to give a solid. The solid waspurified via silica gel chromatography (0 to 80% ethyl acetate inhexanes gradient) to deliver the desired compound, Compound I-405 (262mg, 40% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.08-9.13 (m, 1H), 8.33 (d, 1H),7.49-7.55 (m, 1H), 7.28-7.37 (m, 1H), 7.17-7.25 (m, 2H), 7.10 (t, 1H),6.98 (t, 1H), 5.86-5.92 (m, 2H), 3.92-4.04 (m, 2H).

Compound I-406

The title compound was prepared following general procedure B, except3-methylpiperidine-3-carboxylic acid (as the HCl salt, 1.7 equiv.) wasthe amine reactant, and the contents were heated to 100° C. for 19 h.The reaction mixture was acidified to pH 3 with 1N HCl solution, and theresulting solids were collected by vacuum filtration to deliver thedesired compound, Compound I-406 (95 mg, 94% yield) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.75 (d, 1H), 8.10 (d, 1H), 7.40 (s, 1H), 7.26(app. q, 1H), 7.09 (dd, 1H), 7.03 (app. t, 1H), 6.91 (d, 1H), 6.81 (app.t, 1H), 5.95 (s, 2H), 4.58 (d, 1H), 4.39 (br d, 1H), 3.43 (m, 1H), 3.41(d, 1H), 2.24 (m, 1H), 1.77 (m, 2H), 1.61 (m, 1H), 1.23 (s, 3H).

Compound I-407

The title compound was prepared following general procedure B, except2-aminoethanol (10 equiv.) was the amine reactant, no triethylamine wasused, and the contents were heated to 100° C. for 40 min. The reactionmixture was acidified to pH 3 with 1N HCl solution, and the resultingsolids were collected by vacuum filtration to deliver the desiredcompound, Compound I-407 (57 mg, 58% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ 9.08 (d, 1H), 8.17 (d, 1H), 7.61 (app. t,1H), 7.50 (s, 1H), 7.33 (app. q, 1H), 7.24 (d, 1H), 7.22 (app. t, 1H),7.10 (app. t, 1H), 6.82 (app. t, 1H), 5.89 (s, 2H), 4.78 (t, 1H), 3.58(m, 4H).

Compound I-408

The title compound was prepared following general procedure B, except3-aminopropan-1-ol (10 equiv.) was the amine reactant, no triethylaminewas used, and the contents were heated to 100° C. for 2 h. The reactionmixture was acidified to pH 3 with 1N HCl solution, and the resultingsolids were collected by vacuum filtration to deliver the desiredcompound, Compound I-408 (26 mg, 37% yield) as an off-white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ 9.08 (d, 1H), 8.16 (d, 1H), 7.66 (app. t,1H), 7.49 (s, 1H), 7.32 (app. q, 1H), 7.23 (d, 1H), 7.21 (m, 1H), 7.10(app. t, 1H), 6.83 (app. t, 1H), 5.89 (s, 2H), 4.54 (t, 1H), 3.51 (m,4H), 1.75 (app. quintet, 2H).

Compound I-409

The title compound was synthesized in 2 steps:

Step 1. Synthesis of 1-(((tert-butoxycarbonyl)(ethyl)amino)methyl)cyclopropanecarboxylic acid

A solution of1-(((tert-butoxycarbonyl)amino)methyl)cyclopropanecarboxylic acid in THFat 0° C. was treated with iodoethane (10 equiv.) followed by sodiumhydride (60% w/w mineral oil, 10 equivalents, added in 6 portions).After 2 days, the reaction mixture was carefully quenched with water andwashed with ethyl acetate. The aqueous layer was acidified to pH 3 with3N HCl and extracted with ethyl acetate. The organic phases were driedover sodium sulfate, filtered and the solvent was removed in vacuo toafford1-(((tert-butoxycarbonyl)(ethyl)amino)methyl)cyclopropanecarboxylic acid(92% yield) as a pale yellow oil which was used without furtherpurification.

Step 2. Synthesis of N-((1-carboxycyclopropyl)methyl)ethanaminiumtrifluoroacetate

A solution of1-(((tert-butoxycarbonyl)(ethyl)amino)methyl)cyclopropanecarboxylic acidin dichloromethane was treated with trifluoroacetic acid (30 equiv.).After 2 h, the reaction mixture was concentrated in vacuo to affordN-((1-carboxycyclopropyl)methyl)ethanaminium trifluoroacetate (>99%yield) as a dark yellow oil which was used without further manipulation.

Step 3: Synthesis of Compound I-409

The title compound was prepared following general procedure B, exceptN-((1-carboxycyclopropyl)methyl)ethanaminium trifluoroacetate (1.5equiv.) was the amine reactant, and the contents were heated to 100° C.for 3 d. The crude material was purified via reverse phase HPLC (20-70%acetonitrile/water gradient with 0.1% TFA) to deliver the desiredproduct, Compound I-409 (86 mg, 51% yield) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.82 (d, 1H), 8.28 (d, 1H), 7.52 (s, 1H), 7.30(app. q, 1H), 7.10 (m, 1H), 7.06 (app. t, 1H), 6.97 (d, 1H), 6.96 (m,1H), 6.00 (s, 2H), 4.30 (s, 2H), 4.00 (q, 2H), 1.41 (q, 2H), 1.37 (t,3H), 1.16 (q, 2H).

Compound I-410

The title compound was synthesized in 5 steps:

Step 1: Synthesis of ethyl1-(2-fluorobenzyl)-5-methyl-1H-pyrazole-3-carboxylate

To ethyl 3-methyl-1H-pyrazole-5-carboxylate in DMF was added sodiumhydride (60 wt % in mineral oil, 1.2 equiv.). After 10 min,2-fluorobenzyl bromide (1.2 equiv.) was added and the reaction wasstirred for 20 h. Water was added and the resulting mixture wasextracted with ethyl acetate. The combined organic phases were washedwith water and brine, dried over sodium sulfate, filtered, and thesolvent was removed in vacuo. Purification via silica gel chromatography(10-40% ethyl acetate/hexanes gradient) yielded ethyl1-(2-fluorobenzyl)-5-methyl-1H-pyrazole-3-carboxylate (79% yield) andethyl 1-(2-fluorobenzyl)-3-methyl-1H-pyrazole-5-carboxylate (9% yield).

Step 2: Synthesis of1-(2-fluorobenzyl)-5-methyl-1H-pyrazole-3-carboxylic acid

To a solution of ethyl1-(2-fluorobenzyl)-5-methyl-1H-pyrazole-3-carboxylate in THF/MeOH/Water(3:1:1 ratio) was added lithium hydroxide hydrate (1.5 equiv.). After 23h, the volatile organics were removed in vacuo and the resultant mixturewas acidified to pH 3 with 1N HCl.1-(2-fluorobenzyl)-5-methyl-1H-pyrazole-3-carboxylic acid was collectedby vacuum filtration (92% yield).

Step 3: Synthesis of1-(2-fluorobenzyl)-5-methyl-1H-pyrazole-3-carbonitrile

To a suspension of 1-(2-fluorobenzyl)-5-methyl-1H-pyrazole-3-carboxylicacid, 2-methylpropan-2-amine (3 equiv.), and triethylamine (2 equiv.) inethyl acetate was added n-propylphosphonic anhydride (T3P, 50 wt %solution in ethyl acetate, 3 equiv.). The resultant yellow solution washeated at 65° C. for 2.5 h. The solvent was removed in vacuo. Phosphoryltrichloride (12 equiv.) was added and the resulting mixture was stirredat 70° C. for 1 hour 40 min. The reaction was quenched by carefullypouring into a mixture of water and ice, neutralized to pH 7 by additionof saturated sodium bicarbonate solution and extracted withdichloromethane. The combined organic phases were dried over sodiumsulfate, filtered, and the solvent was removed in vacuo. Purification bysilica gel chromatography (10% ethyl acetate/hexanes gradient) yielded1-(2-fluorobenzyl)-5-methyl-1H-pyrazole-3-carbonitrile (49% yield).

Step 4: Synthesis of1-(2-fluorobenzyl)-5-methyl-1H-pyrazole-3-carboximidamide

A solution of 1-(2-fluorobenzyl)-5-methyl-1H-pyrazole-3-carbonitrile inmethanol was treated sodium methoxide (25 wt % solution in MeOH, 5equiv.) and stirred for 24 h. Ammonium chloride (10 equivalents) wasadded. After 26 hours, the reaction mixture was concentrated in vacuoand partitioned between half-saturated sodium bicarbonate and ethylacetate. The organic phases were dried over sodium sulfate, filtered,and the solvent was removed in vacuo. The crude product was contaminatedwith starting material due to incomplete reaction. This material wasre-subjected to similar conditions to afford1-(2-fluorobenzyl)-5-methyl-1H-pyrazole-3-carboximidamide (92% yield).

Step 5: Synthesis of Compound I-410

A suspension of1-(2-fluorobenzyl)-5-methyl-1H-pyrazole-3-carboximidamide was treatedwith sodium (Z)-3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olate (see alsogeneral procedure A, Step 4, 3.0 equiv.) and heated at 90° C. for 1hour. After cooling to ambient temperature, the reaction mixture wasneutralized by addition of HCl (1.25 M solution in EtOH). The resultanttan suspension was concentrated in vacuo. The residue was partitionedbetween dichloromethane and water and the aqueous layer wasback-extracted with dichloromethane. The combined organic phases weredried over sodium sulfate, filtered, and the solvent was removed invacuo.

Trituration with dichloromethane yielded the titled compound (206 mg,62% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ 12.9 (br s, 1H), 8.07 (br s, 1H), 7.38 (app.q, 1H), 7.25 (m, 1H), 7.18 (app. t, 1H), 7.11 (m, 1H), 6.72 (s, 1H),5.44 (s, 2H), 2.30 (s, 3H).

Compound I-411

The title compound was synthesized in 2 steps:

Step 1: Synthesis of4-chloro-5-fluoro-2-(1-(2-fluorobenzyl)-5-methyl-1H-pyrazol-3-yl)pyrimidine

The intermediate was generated using the procedure described for thesynthesis of Intermediate 1, with the exception of using Compound I-410as the starting pyrimidone. An off-white solid (210 mg, 96% yield) wasobtained, and contents used without further purification.

Step 2: Synthesis of Compound I-411

The title compound was prepared following general procedure B, except1-((methylamino)methyl)cyclopropanecarboxylic acid (as the HCl salt) wasthe amine reactant. The reaction mixture was acidified to pH 3 and theresulting precipitate was collected by vacuum filtration to deliver thedesired compound, Compound I-411 (48 mg, 93% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ 12.3 (s, 1H), 8.16 (d, 1H), 7.36 (app. q,1H), 7.25 (m, 1H), 7.17 (app. t, 1H), 6.99 (app. t, 1H), 6.61 (s, 1H),5.38 (s, 2H), 3.97 (s, 2H), 3.22 (d, 3H), 2.29 (s, 3H), 1.13 (m, 2H),1.01 (m, 2H).

Compound I-412

The title compound was prepared following general procedure B, except(2R,3S)-3-methylpiperidine-2-carboxylic acid was the amine reactant, andcontents were heated to 100° C. for 20 h. The crude material waspurified via reverse phase HPLC (25-80% acetonitrile/water gradient with0.1% TFA) to deliver the desired compound, Compound I-412 (12 mg, 23%yield) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.33 (d, 1H), 7.36 (app. q, 1H), 7.15 (m, 2H),7.06 (app. t, 1H), 6.89 (s, 1H), 5.52 (s, 2H), 5.36 (d, 1H), 4.58 (br s,1H), 3.83 (app. t, 1H), 2.36 (s, 3H), 1.99 (m, 1H), 1.96 (m, 1H), 1.79(m, 2H), 1.58 (m, 1H), 1.24 (d, 3H).

Compound I-413

The title compound was prepared following general procedure B, exceptserinol (10 equiv.) was the amine reactant, and no triethylamine wasused, and contents were heated to 90° C. for 40 min followed by 100° C.for 20 min. The reaction mixture was acidified to pH 3 and the resultingprecipitate was collected by vacuum filtration to deliver the desiredcompound, Compound I-413 (46 mg, 88% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ 8.11 (d, 1H), 7.35 (app. q, 1H), 7.24 (m,1H), 7.16 (app. t, 1H), 7.03 (d, 1H), 6.92 (app. t, 1H), 6.64 (s, 1H),5.40 (s, 2H), 4.71 (t, 2H), 4.24 (m, 1H), 3.56 (m, 4H), 3.12 (s, 3H).

Compound I-414

The title compound was prepared following general procedure B, except2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (2.2 equiv.) was theamine reactant, 5 equivalents of triethylamine was used, and contentswere heated to 90° C. for 18 h followed by 100° C. for 4 d. The crudematerial was purified via reverse phase HPLC (35-80% acetonitrile/watergradient with 0.1% TFA) to deliver the desired compound, Compound I-414(35 mg, 58% yield) as a white solid.

¹H-NMR (500 MHz, MeOH-d₄) δ 8.29 (d, 1H), 7.35 (app. q, 1H), 7.13 (m,3H), 6.79 (s, 1H), 5.50 (s, 2H), 4.29 (s, 2H), 2.36 (s, 3H).

Compound I-416

The title compound was synthesized in 3 steps:

Step 1: Synthesis of3-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-1,2,4-triazin-5(4H)-one

A solution of1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamidehydrochloride in absolute ethanol was treated with hydrazine hydrate(1.5 equiv.) at ambient temperature. After 45 min, ethyl 2-oxoacetate(50 wt % solution in toluene, 3.0 equiv.) was added and the resultantsolution was heated at 50-60° C. for 65 h. The reaction mixture was thenconcentrated in vacuo, taken up in dichloromethane, filtered andconcentrated in vacuo to afford an orange oil. Purification via silicagel chromatography (10-20% acetonitrile-methanol (7:1) indichloromethane) yielded the desired compound3-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-1,2,4-triazin-5(4H)-one (320 mg, 73% yield) as a light tan solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.54 (d, 1H), 7.84 (br s, 1H), 7.44 (s, 1H),7.31 (m, 1H), 7.12-7.04 (m, 3H), 6.63 (d, 1H), 5.95 (s, 2H).

Step 2: Synthesis of3-(3-(5-chloro-1,2,4-triazin-3-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole

3-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-1,2,4-triazin-5(4H)-one was treated with phosphoryl trichloride (42 equivalents,excess). The resultant mixture was heated at 65° C. for 4 h. Theresultant tan suspension was blown dry under a stream of nitrogen anddried azeotropically with toluene. The chloro-triazine was used in thenext step without further manipulation.

Step 3: Synthesis of Compound I-416

The title compound was prepared following general procedure B, exceptserinol (10 equiv.) was the amine reactant,3-(3-(5-chloro-1,2,4-triazin-3-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazolewas used in place of Intermediate 1, no triethylamine was used, andcontents were heated at 100° C. for 24 h as a solution in dioxane/DMSO(7.5:1). The reaction mixture was diluted with water, neutralized to pH4 with 1N HCl solution and extracted with dichloromethane/isopropanol(4:1). The combined organic phases were dried over sodium sulfate,filtered, and the solvent was removed in vacuo. The crude material waspurified via reverse phase HPLC (10-70% acetonitrile/water gradient with0.1% TFA) to deliver the desired compound, Compound I-416 (5.2 mg, 9.8%yield) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.84 (d, 1H), 8.35 (s, 1H), 7.74 (s, 1H), 7.32(app. q, 1H), 7.11 (m, 1H), 7.08 (app. t, 1H), 6.99 (app. t, 1H), 6.96(d, 1H), 6.06 (s, 2H), 4.62 (app. quintet, 1H), 3.84 (m, 4H).

Compound I-417

The title compound was prepared following general procedure B, exceptglycinamide (as the HCl salt, 3.0 equiv.) was the amine reactant, andthe contents were heated to 100° C. for 22 h. The reaction mixture wasacidified to pH 4 with 1N HCl solution, and the resulting solids werecollected by vacuum filtration to deliver the desired compound, CompoundI-417 (110 mg, 94% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ 9.09 (d, 1H), 8.22 (d, 1H), 7.83 (app. t,1H), 7.51 (br s, 1H), 7.48 (s, 1H), 7.31 (app. q, 1H), 7.21 (m, 1H),7.18 (d, 1H), 7.12-7.08 (m, 2H), 6.81 (app. t, 1H), 5.89 (s, 2H), 4.01(d, 2H).

Compound I-418

The title compound was prepared following general procedure B, except3-amino-4,4,4-trifluorobutanoic acid (3 equiv.) was the amine reactant,and contents were heated to 100° C. for 3.5 h then to 120° C. for 18 has a solution in dioxane/DMSO (2:1). Additional 2 equivalents ofIntermediate 1 were added to the reaction, and contents stirred at 120°C. for an additional 4 d. A dichloromethane:isopropanol (4:1) mixturewas used as solvent during work up. The crude material was purified viasilica gel chromatography (5% methanol/dichloromethane isocratic) todeliver the desired compound, Compound I-418 (38 mg, 10% yield) as anoff-white solid.

1H NMR (500 MHz, DMSO-d₆) δ ppm 12.65 (br. s., 1H), 9.09 (d, 1H), 8.35(d, 1H), 8.29 (d, 1H), 7.51 (s, 1H), 7.32 (q, 1H), 7.26 (d, 1H),7.24-7.19 (m, 1H), 7.10 (t, 1H), 6.83 (t, 1H), 5.91 (s, 2H), 5.53 (br.s., 1H), 2.96-2.85 (m, 2H).

Compound I-419

A solution of Compound I-418 in dichloromethane was treated withN,N-diisopropylethylamine (2.0 equiv.) followed byO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 1.2 equiv.). After 15 min, ammonia (0.5 Nsolution in dioxane, 2.0 equiv.) was added and the resultant light brownsuspension was stirred for 1.5 h. The reaction mixture was diluted withwater and extracted with dichloromethane/2-propanol (4:1). The organicphases were dried over magnesium sulfate, filtered and the solvent wasremoved in vacuo. Purification via silica gel chromatography (0-3%methanol/dichloromethane gradient) yielded the desired compound,Compound I-419 (20 mg, 57% yield) as an off-white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ 9.10 (d, 1H), 8.34 (d, 1H), 8.24 (d, 1H),7.51 (m, 2H), 7.32 (app. q, 1H), 7.25 (d, 1H), 7.22 (app. t, 1H), 7.10(app. t, 1H), 7.06 (br s, 1H), 6.82 (app. t, 1H), 5.91 (s, 2H), 5.55 (brs, 1H), 2.77 (dd, 1H), 2.67 (dd, 1H).

Compound I-420

The title compound was prepared in 2 steps:

Step 1: Synthesis of diethyl 2-(dicyanomethyl)-2-methylmalonate

A mixture of diethyl 2-bromo-2-methylmalonate (1 equiv.), malononitrile(1 equiv.) and potassium t-butoxide (1 equiv.) in THF was heated toreflux for 15 h. The mixture was diluted with ethyl acetate andsaturated aqueous ammonium chloride solution and the phases wereseparated. The aqueous phase was extracted twice with ethyl acetate. Thecombined organic phase was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated to give an oil. The oil waspurified by silica gel chromatography (10-15% ethyl acetate in hexanegradient) to give diethyl 2-(dicyanomethyl)-2-methylmalonate (5.76 g,32% yield) as a colorless oil.

¹H NMR (500 MHz, CDCl₃) δ ppm 4.53 (s, 1H), 4.27-4.39 (m, 4H), 1.81 (s,3H), 1.33 (t, 6H).

Step 2: Synthesis of Compound I-420

A mixture of1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamidehydrochloride (generated in step 3 of general procedure A, by using1-(isoxazol-3-yl)ethanone in step 1 and 2-fluorobenzylhydrazine in step2) (1 equiv.), diethyl 2-(dicyanomethyl)-2-methylmalonate (1.15 equiv.)and potassium bicarbonate (2 equiv.) in t-BuOH was heated to reflux for5 h. After cooling, the reaction mixture was added with water andstirred for 30 min. The precipitate was filtered, washed with a minimumamount of water and diethyl ether and dried overnight under high vacuumto give Compound I-420 (385 mg, 52% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.30 (s, 1H), 9.10 (d, 1H), 7.38 (s,1H), 7.29-7.36 (m, 1H), 7.18-7.26 (m, 2H), 7.08-7.14 (m, 1H), 6.81-6.90(m, 1H), 6.65 (br. s., 2H), 5.88 (s, 2H), 4.04-4.16 (m, 2H), 1.59 (s,3H), 1.11 (t, 3H).

Compound I-421

Ammonia (7.0 M in MeOH) (200 equiv.) was added to Compound I-420 (1equiv.). The reaction mixture was heated at 50° C. for 16 h. Theresultant solution was then concentrated in vacuo, and the residue waspurified via reverse phase HPLC (5-60% acetonitrile in water with 1%TFA) to deliver the desired compound, Compound I-421 (24 mg, 63% yield)as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.35 (br. s., 1H), 9.08-9.13 (m, 1H),7.47 (s, 1H), 7.43 (s, 1H), 7.28-7.38 (m, 1H), 7.23-7.27 (m, 1H),7.17-7.23 (m, 2H), 7.06-7.14 (m, 1H), 6.77-7.00 (m, 3H), 5.91 (s, 2H),1.56 (s, 3H).

Compound I-422

Cyclopropyl amine (150 equiv.) was added to Compound I-420 (1 equiv.),and the reaction mixture was heated at 50° C. for 30 h. The resultantsolution was then concentrated in vacuo, and the residue was purified byreverse phase HPLC (25-50% acetonitrile in water with 1% TFA) to deliverthe desired compound, Compound I-422 (29 mg, 57% yield) as a whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.29 (br. s., 1H), 9.11 (d, 1H),7.59-7.66 (m, 1H), 7.42 (s, 1H), 7.29-7.37 (m, 1H), 7.16-7.28 (m, 2H),7.06-7.15 (m, 1H), 6.65-6.89 (m, 3H), 5.90 (s, 2H), 2.59-2.69 (m, 1H),1.54 (s, 3H), 0.53-0.65 (m, 2H), 0.39-0.52 (m, 2H).

Compound I-423

The title compound was prepared following general procedure B, except4-(piperidin-4-ylsulfonyl)morpholine (as the TFA salt, 1.7 equiv.) wasthe amine reactant, 4 equivalents of triethylamine was used, and thecontents were heated to 105° C. for 12 h. Ethyl acetate was the solventused for work up. The crude material was purified via silica gelchromatography using a 1 to 5% methanol in dichloromethane gradient over40 minutes to deliver the desired compound, Compound I-423 (32.7 mg, 35%yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.48 (d, 1H), 8.25 (d, 1H), 7.30 (s,1H), 7.20-7.25 (m, 1H), 7.03-7.08 (m, 1H), 6.96-7.01 (m, 1H), 6.83-6.88(m, 1H), 6.60 (d, 1H), 5.98 (s, 2H), 4.83 (d, 2H), 3.76 (m, 4H), 3.41(m, 4H), 3.23-3.29 (m, 1H), 3.06-3.11 (m, 2H), 2.20-2.26 (m, 2H),1.91-2.03 (m, 2H).

Compound I-424

The title compound was prepared following general procedure B, excepttrans-4-(trifluoromethyl)pyrrolidine-3-carboxylic acid (as the TFA salt,1.5 equiv.) was the amine reactant, 4 equivalents of triethylamine wasused, and the contents were heated to 105° C. for 3 h. Adichloromethane:isopropanol mix (5:1) was used as solvent for work up.Concentration of the dried and filtered organic layer in vacuo deliveredthe desired compound, Compound I-424 (108.3 mg, 89% yield) as anoff-white solid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.50 (d, 1H), 8.18 (d, 1H), 7.40 (s,1H), 7.19-7.25 (m, 1H), 6.98-7.07 (m, 3H), 6.65 (d, 1H), 5.94 (s, 2H),4.26 (m, 1H), 4.11-4.18 (m, 2H), 4.03-4.09 (m, 1H), 3.48-3.55 (m, 1H),3.39-3.54 (m, 1H).

Compound I-425

To a suspension of Compound I-366 (1 equiv.) in dichloromethane wasadded cyclopropanecarboxylic acid chloride (1.08 equiv.) andtriethylamine (1.1 equiv.). After stirring at room temperature for 24 h,the reaction was still heterogeneous and incomplete by LC/MS analysis.An additional 4 equivalents of the acid chloride and1,8-Diazabicycloundec-7-ene were added, and the reaction was then heatedto 60° C. for 1 h, after which the reaction was tan in color andcompletely homogeneous. The reaction was diluted in water, acidified bythe addition of 1N hydrochloric acid solution, extracted withdichloromethane (3×), dried (sodium sulfate), filtered and concentratedto afford a white solid. Purification was achieved by silica gel using 1to 8% methanol in dichloromethane over 38 minutes to deliver the desiredcompound, Compound I-425 (40.4 mg, 71% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.47 (d, 1H), 8.23 (d, 1H), 7.82 (br.s, 1H), 7.29 (s, 1H), 7.17-7.23 (m, 1H), 7.01-7.06 (m, 1H), 6.95-6.99(m, 1H), 6.81-6.87 (m, 1H), 6.60 (d, 1H), 5.96 (s, 2H), 4.79-4.84 (m,2H), 3.83-3.94 (m, 1H), 3.08-3.15 (m, 2H), 2.23-2.29 (m, 2H), 2.01-2.06(m, 1H), 1.27 (m, 2H), 1.19 (m, 2H), 0.99-1.04 (m, 2H).

Compound I-426

To a suspension of Compound I-366 (1 equiv.) in dichloromethane wasadded acetic anhydride (1.25 equiv.) and 1,8-Diazabicycloundec-7-ene(1.25 equiv.). After stirring at room temperature for 24 h, the reactionwas still heterogeneous and incomplete by LC/MS. An additional 4equivalents of acetic anhydride and 1,8-Diazabicycloundec-7-ene wereadded, and the reaction was then heated to 60° C. for 1 h, after whichthe reaction was tan in color and completely homogeneous. The reactionwas diluted in water, acidified by the addition of 1N hydrochloric acidsolution, extracted with dichloromethane (3×), dried (sodium sulfate),filtered and concentrated to afford a white solid. Purification wasachieved by silica gel chromatography using a 1 to 8% methanol indichloromethane gradient over 38 minutes to deliver the desiredcompound, Compound I-426 (24.7 mg, 44% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.47 (d, 1H), 8.23 (d, 1H), 7.85 (br.s, 1H), 7.29 (s, 1H), 7.18-7.25 (m, 1H), 7.02-7.08 (m, 1H), 6.96-7.02(m, 1H), 6.84-6.89 (m, 1H), 6.61 (d, 1H), 6.00 (s, 2H), 4.80-4.90 (m,2H), 3.85-3.95 (m, 1H), 3.08-3.17 (m, 2H), 2.23-2.31 (m, 2H), 2.17 (s,3H), 1.97-2.08 (m, 2H).

Compound I-427

The title compound was prepared following general procedure B, exceptpyrrolidine-3-sulfonamide (1.35 equiv.) was the amine reactant, 4equivalents of triethylamine was used, and the contents were heated to105° C. for 2 h. After cooling, the reaction was poured into a 1:1 mixof water and ethyl acetate, and the resulting precipitate was filteredand dried in vacuo delivered the desired compound, Compound I-427 (46.7mg, 39% yield) as an off-white solid.

¹H NMR (500 MHz, DMSO-d₆) δ (ppm): 9.05-9.13 (m, 1H), 8.24-8.31 (m, 1H),7.51-7.57 (m, 1H), 7.28-7.37 (m, 1H), 7.18-7.27 (m, 2H), 7.06-7.17 (m,3H), 6.76-6.87 (m, 1H), 5.87-5.93 (m, 2H), 4.00-4.09 (m, 2H), 3.84-3.97(m, 2H), 3.75-3.84 (m, 1H), 2.29-2.42 (m, 2H).

Compound I-428

The title compound was prepared following general procedure B, exceptdiethanolamine (1.3 equiv.) was the amine reactant, 2 equivalents oftriethylamine was used, and the contents were heated to 100° C. for 12h. A dichloromethane:isopropanol mix (5:1) was used as solvent for workup. The crude material was purified via silica gel chromatography usinga 1 to 8% methanol in dichloromethane gradient over 40 minutes todeliver the desired compound, Compound I-428 (24.7 mg, 26% yield) as awhite solid.

¹H NMR (500 MHz, CD₃OD) δ (ppm): 8.48 (d, 1H), 8.17 (d, 1H), 7.24 (s,1H), 7.18-7.23 (m, 1H), 7.01-7.06 (m, 1H), 6.96-7.01 (m, 1H), 6.87-6.92(m, 1H), 6.58 (d, 1H), 5.95 (s, 2H), 3.99 (m, 4H), 3.89 (m, 4H), 3.30(br. s, 2H).

Compound I-429

To a solution of Compound I-427 (1 equiv.), in dichloromethane was addedcyclopropanecarboxylic acid chloride (6 equiv.) followed by1,8-diazabicycloundec-7-ene (8 equiv.). The reaction was heated for 1 hat 100° C. after which it was cooled, diluted in water and 1Mhydrochloric acid solution, extracted with dichloromethane (2×),concentrated and purified directly via silica gel chromatography using a1 to 8% methanol in dichloromethane gradient over 40 minutes to deliverthe desired compound, Compound I-429 (26.5 mg, 70% yield) as a whitesolid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.47 (d, 1H), 8.18 (d, 1H), 7.31 (s,1H), 7.18-7.23 (m, 1H), 7.01-7.06 (m, 1H), 6.96-7.01 (m, 1H), 6.83-6.88(m, 1H), 6.60 (d, 1H), 5.97 (s, 2H), 4.40-4.47 (m, 2H), 4.04-4.15 (m,2H), 3.90-3.97 (m, 1H), 2.65-2.73 (m, 1H), 2.45-2.53 (m, 1H), 1.30 (m,1H), 1.17 (m, 2H), 0.99 (m, 2H).

Compound I-430

The title compound was prepared following general procedure B, except(2R,3R)-2-(hydroxymethyl)pyrrolidin-3-ol (as the TFA salt, 1.7 equiv.)was the amine reactant, 4 equivalents of triethylamine was used, and thecontents were heated to 100° C. for 2 h. After cooling, the reaction wasdiluted with water and methanol, and the resulting precipitate wasfiltered, washed with water, and dried in vacuo to deliver the desiredcompound, Compound I-430 (79.3 mg, 64% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ (ppm): 9.09 (d, 1H), 8.24 (d, 1H), 7.51 (s,1H), 7.30-7.36 (m, 1H), 7.19-7.25 (m, 2H), 7.08-7.13 (m, 1H), 6.82-6.87(m, 1H), 5.90 (d, 1H), 5.85 (d, 1H), 5.23 (d, 1H), 4.71 (br. s, 1H),4.35-4.42 (m, 1H), 4.15-4.20 (m, 1H), 3.77-3.87 (m, 2H), 3.64-3.74 (m,2H), 2.04-2.09 (m, 2H).

Compound I-431

The title compound was prepared following general procedure B, exceptdiisopropanolamine (1 equiv.) was the amine reactant, 4 equivalents oftriethylamine was used, and the contents were heated to 100° C. for 24h. Ethyl acetate was used as solvent for work up. The crude material waspurified via silica gel chromatography using a 1 to 8% methanol indichloromethane gradient over 40 minutes to deliver the desiredcompound, Compound I-431 (47.1 mg, 42% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ (ppm): 8.72 (d, 1H), 8.11 (d, 1H), 7.35 (s,1H), 7.23-7.28 (m, 1H), 7.05-7.11 (m, 1H), 7.01-7.05 (m, 1H), 6.83-6.88(m, 2H, 2 shifts isochronous), 5.96 (d, 1H), 5.92 (d, 1H), 4.10-4.21 (m,2H), 3.90-3.97 (m, 2H), 3.61-3.67 (m, 2H), 1.21 (s, 6H).

Compound I-432

The title compound was prepared in 3 steps:

Step 1: Synthesis of2-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)ethanesulfonicacid

The intermediate was prepared following general procedure B, excepttaurine (1.3 equiv.) was the amine reactant, 2 equivalents oftriethylamine was used, and the contents were heated to 100° C. for 8 h.After cooling, the reaction was diluted with 1N HCl solution, filtered,washed with water, and dried in vacuo to deliver the desiredintermediate,2-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)ethanesulfonicacid (60.2 mg, 64% yield) as a white solid. The intermediate was usedwithout further purification.

Step 2: Synthesis of2-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)ethanesulfonylchloride

A suspension of2-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)ethanesulfonicacid (1 equiv.) and thionyl chloride (5 equiv.) in dichloromethane wasstirred at room temperature, after which 2 drops of DMF were added. Thesuspension was heated to 60° C. for 12 h, after which LC/MS indicatedthat the sulfonyl chloride had formed. The reaction mixture wasconcentrated to dryness to afford 90 mg of an off-white solid.

Step 3: Synthesis of Compound I-432

To a suspension of the crude2-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)ethanesulfonylchloride in tetrahydrofuran was added a 50% aqueous solution ofhydroxylamine (10 equiv.). The reaction became homogeneous instantly,and was shown by LC/MS to be complete. The reaction was concentrated toone third of its volume and purified directly on silica gel using 3 to10% methanol in dichloromethane over 45 minutes to deliver the desiredcompound, Compound I-432 (8.2 mg, 25% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ (ppm): 8.76 (d, 1H), 8.13 (d, 1H), 7.60 (s,1H), 7.25-7.31 (m, 1H), 7.07-7.13 (m, 1H), 7.03-7.07 (m, 1H), 6.89 (d,1H), 6.83-6.88 (m, 1H), 6.00 (s, 2H), 4.07 (t, 2H), 3.62 (t, 2H).

Compound I-433

The title compound was prepared following general procedure B, exceptpiperidine-3,5-dione (as the HCl salt, 1.4 equiv.) was the aminereactant, 4 equivalents of triethylamine was used, and the contents wereheated to 100° C. for 1 h. Ethyl acetate was used as solvent for workup. The crude material was purified via silica gel chromatography usinga 3 to 20% methanol in dichloromethane gradient over 40 minutes todeliver the desired compound, Compound I-433 (45.6 mg, 44% yield) as awhite solid.

¹H NMR (500 MHz, CD₃OD) δ (ppm): 8.77 (s, 1H), 8.30 (d, 1H), 7.50 (s,1H), 7.26-7.32 (m, 1H), 7.07-7.13 (m, 1H), 7.03-7.07 (m, 1H), 6.94 (d,1H), 6.83-6.88 (m, 1H), 5.98 (s, 2H), 4.58 (s, 4H).

Compound I-434

The title compound was prepared following general procedure B, except4-(hydroxymethyl)piperidin-4-ol (as the HCl salt, 1.4 equiv.) was theamine reactant, 4 equivalents of triethylamine was used, and thecontents were heated to 100° C. for 1 h. After cooling, the reaction wasdiluted with water and 1N HCl solution, and the resulting precipitatewas filtered, washed with water, and dried in vacuo to deliver thedesired compound, Compound I-434 (88.5 mg, 82% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ (ppm): 8.77 (d, 1H), 8.15 (d, 1H), 7.43 (s,1H), 7.23-7.30 (m, 1H), 7.06-7.12 (m, 1H), 7.00-7.05 (m, 1H), 6.91 (d,1H), 6.79-6.84 (m, 1H), 5.96 (s, 2H), 4.49-4.57 (m, 2H), 3.49-3.57 (m,2H), 3.40 (s, 2H), 1.65-1.71 (m, 2H), 1.77-1.84 (m, 2H).

Compound I-435

The title compound was prepared following general procedure B, except(3R,5S)-5-(hydroxymethyl)pyrrolidin-3-ol (2.7 equiv.) was the aminereactant, 4 equivalents of triethylamine was used, and the contents wereheated to 100° C. for 30 min. After cooling, the reaction was dilutedwith water and methanol, and the resulting precipitate was filtered,washed with water, and dried in vacuo to deliver the desired compound,Compound I-435 (77.3 mg, 87% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ (ppm): 8.75 (d, 1H), 8.12 (d, 1H), 7.40 (s,1H), 7.24-7.28 (m, 1H), 7.06-7.10 (m, 1H), 7.01-7.05 (m, 1H), 6.90 (d,1H), 6.80-6.85 (m, 1H), 5.95 (s, 2H), 4.63-4.68 (m, 1H), 4.53-4.57 (m,1H), 3.81-3.94 (m, 3H), 3.73-3.80 (m, 1H), 2.10-2.25 (m, 2H).

Compound I-437

This compound was made in two steps

Step 1: Ketal Intermediate

To a suspension of the crude2-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)ethanesulfonylchloride (synthesis described in Step 2 of procedure for making CompoundI-432 (1 equiv.) in dioxane was added(S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (2 equiv.). The reactionwas stirred for 24 h, after which the reaction mixture was diluted in5:1 dichloromethane/isopropanol and acidified by the addition of 1Mhydrochloric acid, extracted with 5:1 dichloromethane/isopropanol (3×30mL), dried (sodium sulfate), filtered and concentrated to afford aresidue. Purification was achieved via silica gel chromatography using a7 to 12% methanol in dichloromethane gradient over 45 minutes to deliverthe desired compound, Compound I-43 (31.0 mg, 42% yield) as white solid.

¹H NMR (500 MHz, CD₃OD) δ (ppm): 8.78 (d, 1H), 8.13 (d, 1H), 7.52 (s,1H), 7.26-7.32 (m, 1H), 7.10-7.15 (m, 1H), 7.04-7.08 (m, 1H), 6.91 (d,1H), 6.80-6.85 (m, 1H), 6.00 (s, 2H), 4.16-4.20 (m, 1H), 4.03-4.12 (m,2H), 3.98-4.02 (m, 1H), 3.70-3.74 (m, 1H), 3.45-3.52 (m, 2H), 3.22 (d,2H), 1.34 (s, 3H), 1.27 (s, 3H).

Step 2: Compound I-437

To a solution of the intermediate prepared in step 1 (1 equiv.) indichloromethane was added a 4M in dioxane solution of hydrogen chloride(20 equiv.). After 1 h, the reaction was concentrated to dryness,diluted in water, extracted with 5:1 dichloromethane/isopropanol (3×),dried (sodium sulfate), filtered, and concentrated to afford a residue.Purification was achieved via silica gel chromatography to deliver thedesired compound, Compound I-437 (10.3 mg, 38.2% yield) as an off-whitesolid.

¹H NMR (500 MHz, CD₃OD) δ (ppm): 8.77 (d, 1H), 8.12 (d, 1H), 7.53 (s,1H), 7.26-7.32 (m, 1H), 7.08-7.13 (m, 1H), 7.03-7.08 (m, 1H), 6.93 (d,1H), 6.81-6.86 (m, 1H), 6.00 (s, 2H), 4.03-4.13 (m, 2H), 3.70-3.75 (m,1H), 3.47-3.54 (m, 3H), 3.24-3.29 (m, 2H), 3.08-3.13 (m, 1H).

Compound I-438

The title compound was prepared following general procedure B, except4-hydroxypiperidine-4-carboxamide (1.4 equiv.) was the amine reactant, 4equivalents of triethylamine was used, and the contents were heated to100° C. for 30 min. Ethyl acetate was used as solvent for work up, andpurification was achieved by precipitation of the product by triturationof an acetonitrile solution of the crude product with water. Theresulting precipitate was filtered and dried in vacuo to deliver thedesired compound, Compound I-438 (26.3 mg, 26% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ (ppm): 9.08 (d, 1H), 8.29 (d, 1H), 7.55 (s,1H), 7.30-7.35 (m, 2H, 2 shifts isochronous), 7.26 (d, 2H), 7.19-7.25(m, 1H), 7.16 (br. s, 1H), 7.08-7.13 (m, 1H), 6.79-6.84 (m, 1H), 5.90(s, 2H), 4.39 (m, 2H), 3.34-3.39 (m, 2H), 1.95-2.01 (m, 2H), 1.58 (m,2H).

Compound I-439

To a suspension of the2-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)ethanesulfonylchloride (synthesis described in Step 2 of procedure for Compound I-432,1 equiv.) in dioxane was added ethanolamine (2.2 equiv.). The reactionwas stirred for 24 h at room temperature, after which the reactionmixture was diluted in 5:1 dichloromethane/isopropanol and acidified bythe addition of 1M hydrochloric acid, extracted with 5:1dichloromethane/isopropanol (3×), dried (sodium sulfate), filtered andconcentrated to afford a residue. Purification was achieved via silicagel chromatography using a 3 to 8% methanol gradient in dichloromethaneover 45 minutes to deliver the desired compound, Compound I-439 (31.3mg, 65% yield) as white solid.

¹H NMR (500 MHz, DMSO-d₆) δ (ppm): 9.09 (d, 1H), 8.24 (d, 1H), 7.78-7.83(m, 1H), 7.54 (s, 1H), 7.30-7.35 (m, 1H), 7.21-7.25 (m, 2H), 7.17 (d,1H), 7.08-7.13 (m, 1H), 6.81-6.86 (m, 1H), 5.90 (s, 2H), 4.80 (t, 1H),3.84 (q, 2H), 3.44 (q, 2H), 3.39 (t, 2H), 3.03 (q, 2H).

Compound I-440

The title compound was synthesized in 2 steps:

Step 1: Synthesis of1-(benzyloxy)-N-(1-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)azetidin-3-yl)cyclopropanecarboxamide

The intermediate was prepared following general procedure B, exceptN-(azetidin-3-yl)-1-(benzyloxy)cyclopropanecarboxamide (as the TFA salt,1.2 equiv.) was the amine reactant, 4 equivalents of triethylamine wasused, and the contents were heated to 100° C. for 2 h. After cooling,the reaction mixture was diluted with water, and the resultingprecipitate was filtered, washed with water, and dried in vacuo todeliver the desired intermediate,1-(benzyloxy)-N-(1-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)azetidin-3-yl)cyclopropanecarboxamide(104.3 mg, 86% yield) as a white solid.

Step 2: Synthesis of Compound I-440

To a suspension of1-(benzyloxy)-N-(1-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)azetidin-3-yl)cyclopropanecarboxamidein ethanol was added 10% Palladium on Carbon (0.1 equiv). The reactionmixture was evacuated to dryness and a hydrogen balloon was applied. Forsolubility purposes, ethyl acetate was also added. After 24 h, a mixtureof starting material, product and other byproducts were observed. Thereaction mixture was filtered through celite, then purified via silicagel chromatography using a 1 to 8% dichloromethane in methanol gradientover 60 minutes to deliver the desired compound, Compound I-440 (3.8 mg,5% yield). Several later fractions containing the desired product werecontaminated with a close-running byproduct and discarded.

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.44 (d, 1H), 8.09 (d, 1H), 7.92 (br.s, 1H), 7.20-7.25 (m, 1H), 6.93-7.03 (m, 2H, 2 shifts isochronous),6.83-6.88 (m, 2H), 6.56 (d, 1H), 5.94 (s, 2H), 4.81-4.91 (m, 1H),4.55-4.63 (m, 1H), 4.05-4.12 (m, 2H), 2.31-2.36 (m, 1H), 1.33-1.37 (m,2H), 1.04-1.09 (m, 2H).

Compound I-441

The title compound was prepared following general procedure B, except3-(aminomethyl)-1H-1,2,4-triazol-5 (4H)-one (1.3 equiv.) was the aminereactant, 4 equivalents of triethylamine was used, and the contents wereheated to 100° C. for 12 h. After cooling, the reaction was filtered andpurified via silica gel chromatography using a 3 to 10% methanol indichloromethane gradient over 40 minutes to deliver the desiredcompound, Compound I-441 (12.9 mg, 13% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ (ppm): 8.78 (d, 1H), 8.17 (m, 1H), 7.42 (s,1H), 7.25-7.31 (m, 1H), 7.07-7.12 (m, 1H), 7.02-7.07 (m, 1H), 6.88-6.93(m, 2H, 2 shifts isochronous), 6.02 (s, 2H), 4.61 (s, 2H).

Compound I-442

To a suspension of 1,2,4-Triazolin-3-one (0.5 equiv.), potassiumcarbonate (1.5 equiv.), and copper (I) iodide (0.05 equiv.) inN,N-Dimethylformamide was added Intermediate 1 (1 equiv.) followed bytrans-1,2-bis(methylamino)cyclohexane (0.1 equiv.). The reaction washeated to 100° C. for 24 h, after which the reaction was diluted inwater, extracted with ethyl acetate, dried (sodium sulfate), filteredand concentrated. Two purification attempts were made by silica gelchromatography (5-7% methanol in dichloromethane), leading to one peakthat was a composite of three compounds. Further purification by reversephase HPLC (5 to 75% acetonitrile in water spiked with 0.1%trifluoroacetic acid over 20 minutes) delivered the desired compound,Compound I-442 (0.9 mg, 0.8% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ (ppm): 8.96 (s, 1H), 8.81 (d, 1H), 8.12 (s,1H), 7.66 (s, 1H), 7.25-7.31 (m, 1H), 7.09-7.15 (m, 1H), 7.02-7.07 (m,1H), 6.89-6.94 (m, 1H), 5.98 (s, 2H).

Compound I-443

The title compound was prepared following general procedure B, except3-amino-2-hydroxypropanamide (2 equiv.) was the amine reactant, 4equivalents of triethylamine was used, and the contents were heated to110° C. for 6 h. A dichloromethane:isopropanol mix (5:1) was used assolvent for work up. The crude material was purified via silica gelchromatography using a 3 to 10% methanol in dichloromethane gradientover 45 minutes to deliver the desired compound, Compound I-443 (17.3mg, 14% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ (ppm): 8.78 (d, 1H), 8.11 (d, 1H), 7.52 (s,1H), 7.27-7.31 (m, 1H), 7.09-7.13 (m, 1H), 7.03-7.08 (m, 1H), 6.95 (d,1H), 6.83-6.88 (m, 1H), 5.99 (s, 2H), 4.37 (dd, 1H), 4.05 (dd, 1H), 3.81(dd, 1H).

Compound I-444

To a solution of Intermediate-2 (intermediate described in patentapplication publication WO2012/3405 A1) (1 equiv.) in dichloromethanewas added 2,2,2-trifluoroethane sulfonyl chloride (1.08 equiv.) followedby 1,8-diazabicycloundec-7-ene (1.2 equiv.). The reaction was allowed tostir 16 h at 23° C., after which the reaction mixture was diluted inwater and 1N hydrochloric acid solution, extracted with ethyl acetate(3×), washed with 1N hydrochloric acid solution (2×), dried (sodiumsulfate), filtered and concentrated in vacuo. Purification of the crudematerial via silica gel chromatography using isocratic 5% methanol indichloromethane gradient delivered the desired compound, Compound I-444(28.9 mg, 27% yield) as an off-white solid.

¹H NMR (500 MHz, CD₃OD) δ (ppm): 8.82 (d, 1H), 8.24 (br. s, 1H), 7.57(s, 1H), 7.26-7.32 (m, 1H), 7.08-7.13 (m, 1H), 7.03-7.08 (m, 1H),6.93-6.99 (m, 2H, 2 overlapping shifts), 6.79-6.85 (br. s, 1H), 6.01 (s,2H), 4.49-4.58 (m, 2H).

Compound I-445

To a suspension of sodium hydride (1.2 equiv.) in anhydroustetrahydrofuran at 23° C. was added Intermediate-2 (1 equiv.). Thereaction was allowed to stir 30 min at 23° C.3,3,3-Trifluoropropane-1-sulfonyl chloride (1 equiv.) dissolved intetrahydrofuran was added to the reaction mixture which was stirred for18 h. The reaction mixture was diluted in water and 1N hydrochloric acidsolution, extracted with ethyl acetate (3×), washed with 1N hydrochloricacid solution (2×), dried (sodium sulfate), filtered and concentrated invacuo. Purification of the crude material via reverse phase HPLCdelivered the desired compound, Compound I-445 (17.1 mg, 20% yield) asan off-white solid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.51 (d, 1H), 8.25 (br. s, 1H),7.20-7.29 (m, 2H), 6.98-7.08 (m, 3H), 6.59 (d, 1H), 5.80-5.99 (m, 2H),3.64 (br. s, 2H), 2.69-2.88 (m, 2H).

Compound I-446

To a suspension of sodium hydride (1.2 equiv.) in anhydroustetrahydrofuran at 23° C. was added Intermediate-21 equiv.). Thereaction was allowed to stir 30 min at 23° C. 2-Methoxyethanesulfonylchloride (1 equiv.) dissolved in tetrahydrofuran was added to thereaction mixture which was stirred for 18 h. The reaction mixture wasdiluted in water and 1N hydrochloric acid solution, extracted with ethylacetate (3×), washed with 1N hydrochloric acid solution (2×), dried(sodium sulfate), filtered and concentrated. Purification of the crudematerial via reverse phase HPLC delivered the desired compound, CompoundI-446 (9.1 mg, 13.5% yield) as an off-white solid.

¹H NMR (500 MHz, CDCl₃) δ (ppm): 8.50 (d, 1H), 8.37 (br. s, 1H),7.19-7.27 (m, 2H), 6.92-7.07 (m, 3H), 6.61 (d, 1H), 5.94 (s, 2H),3.85-3.92 (m, 2H), 3.78 (br. s, 2H), 3.28 (s, 3H).

Compound I-447

Oxalyl chloride (4 equiv.) was added to a solution of triethylamine (4equiv.) and Compound I-214 (1 equiv.) in DCM maintained at 0° C. Thereaction was warmed and stirred at room temperature for 2 h. Thereaction was then quenched by addition of water, extracted withdichloromethane, and organic extracts were concentrated in vacuo todeliver the desired compound, Compound I-447 (3.7 mg, 69% yield) as asolid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.11 (d, 1H), 8.90 (d, 1H), 7.65 (s,1H), 7.30-7.37 (m, 1H), 7.27 (d, 1H), 7.19-7.26 (m, 1H), 7.11 (t, 1H),6.87 (t, 1H), 5.93 (s, 2H), 4.00-4.07 (m, 2H), 2.57 (t, 2H), 2.13-2.21(m, 2H).

Compound I-448

The title compound was prepared following general procedure B, except5-(aminomethyl)thiophene-2-carboxylic acid (4 equiv.) was the aminereactant, 9 equivalents of triethylamine was used, and the contents wereheated to 110° C. as a solution in dioxane/water (4.5:1) for 2 d.Contents diluted with ethyl acetate and 1N HCl solution, and theresulting precipitate was filtered. The solids were collected and driedin vacuo to deliver the desired compound, Compound I-448 (12 mg, 27%yield) as a solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.9 (br. s., 1H), 9.11 (d, 1H),8.92-9.08 (m, 1H), 8.35 (t, 1H), 7.61-7.67 (m, 1H), 7.56 (d, 1H),7.30-7.38 (m, 1H), 7.19-7.26 (m, 3H), 7.12 (t, 1H), 6.92 (t, 1H), 5.92(s, 2H), 4.88-4.97 (m, 2H).

Compound I-449

The title compound was prepared following general procedure B, except5-aminopentanoic acid (4 equiv.) was the amine reactant, 9 equivalentsof triethylamine was used, and the contents were heated to 110° C. as asolution in dioxane/water (4.5:1) for 2 d. Contents diluted with ethylacetate and 1N HCl solution, and the resulting precipitate was filtered.The solids were collected and dried in vacuo to deliver the desiredcompound, Compound I-449 (34 mg, 84% yield) as a solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.01 (s, 1H), 9.12 (s, 1H), 8.32-8.62(m, 1H), 8.27 (br. s., 1H), 7.61 (br. s., 1H), 7.29-7.40 (m, 1H),7.18-7.27 (m, 2H), 7.11 (t, 1H), 6.88 (t, 1H), 5.93 (br. s., 2H), 2.29(t, 3H), 1.49-1.72 (m, 5H).

Compound I-450

A suspension of5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-pyrimidin-4-ol(generated via general procedure A, using 1-(isoxazol-3-yl)ethanone instep 1 and 2-fluorobenzylhydrazine in step 2) (1 equiv.) and sodiummethoxide in methanol (0.5 M solution, 4 equiv.) was heated in amicrowave vessel at 130° C. for 4 h. The reaction was quenched with 1NHCl solution to pH 2, and the resulting residue was filtered. The solidswere washed with methanol and dried in vacuo to deliver the desiredcompound, Compound I-450 (1.45 g, 68%) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.04 (d, 1H), 7.71 (s, 1H), 7.23-7.36 (m,1H), 7.00-7.18 (m, 2H), 6.90 (t, 1H), 5.94 (s, 2H), 2.56 (s, 3H)

Compound I-451

The title compound was prepared in 2 steps:

Step 1: Synthesis of1-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)ethanone

Compound I-450 was charged with phosphoryl trichloride (60 equiv.) andthe resulting mixture was stirred at 45° C. until the reaction wasjudged complete by LC/MS. The reaction was then carefully poured overice, extracted with 4:1 dichloromethane/isopropanol and the layers wereseparated. The organic portions were combined, dried with sodiumsulfate, filtered, and concentrated in vacuo. The material was carriedforward into the next step without further purification.

Step 2: Synthesis of Compound I-451

The title compound was prepared following general procedure B, except1-((methylamino)methyl)cyclopropanecarboxylic acid was the aminereactant,1-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)ethanonewas used in place of Intermediate 1, and contents were heated to 100° C.for 36 h as a solution in dioxane. The crude material was purified viareverse phase HPLC to deliver the desired compound, Compound I-451 (50mg, 69% yield) as a tan solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.53 (br. s, 1H), 8.19 (d, 1H), 7.65(s, 1H), 7.33 (d, 1H), 7.17-7.26 (m, 1H), 7.11 (t, 1H), 6.86 (t, 1H),5.81 (s, 2H), 4.00 (s, 2H), 3.24 (d, 3H), 2.57 (s, 3H), 1.03 (d, 2H),0.74-0.91 (m, 2H).

Compound I-452 and Compound I-453

The title compound was prepared following general procedure B, except4-(trifluoromethyl)piperidine-2-carboxylic acid was the amine reactant,Hunig's base (8 equiv.) was used in place of triethylamine, and thecontents were heated to 120° C. for 18 h as a solution in THF/water(1:1). Solvent removed in vacuo, and the resulting residue was purifiedvia reverse phase HPLC, then with silica gel chromatography utilizing a0-10% methanol/dichloromethane gradient to deliver the desiredcompounds, Compound I-452 (14 mg, 15% yield) as a solid and CompoundI-453 (18.4 mg, 21% yield) as a solid. Assignment of trans vs. cis wasmade in an arbitrary manner at time of synthesis; each diastereomer is amix of racemates.

¹H NMR of Compound I-452 (500 MHz, CD₃OD) δ 8.72-8.79 (m, 1H), 8.20-8.25(m, 1H), 7.41-7.47 (m, 1H), 7.22-7.32 (m, 1H), 6.99-7.14 (m, 2H),6.87-6.92 (m, 1H), 6.76-6.84 (m, 1H), 5.93-5.99 (m, 2H), 5.59-5.76 (m,1H), 4.64-4.80 (m, 1H), 3.38-3.46 (m, 1H), 2.55-2.63 (m, 1H), 2.40-2.54(m, 1H), 2.00-2.08 (m, 1H), 1.84-1.96 (m, 1H), 1.64-1.75 (m, 1H).

¹H NMR of Compound I-453 (500 MHz, CD₃OD) δ 8.73-8.79 (m, 1H), 8.23-8.33(m, 1H), 7.43 (s, 1H), 7.24-7.31 (m, 1H), 7.07-7.13 (m, 1H), 7.00-7.06(m, 1H), 6.82-6.88 (m, 2H), 5.96 (s, 2H), 4.52-4.60 (m, 1H), 4.05-4.14(m, 1H), 3.75-3.85 (m, 1H), 2.64-2.78 (m, 1H), 2.41-2.49 (m, 1H), 2.12(dd, 2H), 1.77-1.87 (m, 1H).

Compound I-454

The title compound was prepared following general procedure B, except3-(trifluoromethyl)piperidine-2-carboxylic acid (5 equiv.) was the aminereactant, and the contents were heated to 90° C. for 18 h as a solutionin THF/water (3:1). Solvent removed in vacuo, and the resulting residuewas purified via reverse phase HPLC, then with silica gel chromatographyutilizing a 0-15% methanol/dichloromethane gradient to deliver thedesired compound, Compound I-454 (1.6 mg, 4% yield) as a solid

¹H NMR (500 MHz, CD₃OD) δ ppm 8.76-8.80 (m, 1H), 8.28-8.33 (m, 1H), 7.49(s, 1H), 7.25-7.32 (m, 1H), 7.02-7.13 (m, 2H), 6.84-6.90 (m, 2H),5.94-6.00 (m, 2H), 5.37-5.41 (m, 1H), 4.35-4.43 (m, 1H), 3.80-3.89 (m,1H), 2.89-3.00 (m, 1H), 1.93-2.08 (m, 3H), 1.77-1.90 (m, 1H).

Compound I-455

The title compound was prepared following general procedure B, except3-ethylpiperidine-2-carboxylic acid (1 equiv.) was the amine reactant,and the contents were heated to 90° C. for 18 h as a solution inTHF/water (5:1). Solvent removed in vacuo, and the resulting residue waspurified via reverse phase HPLC to deliver the desired compound,Compound I-455 (5 mg, 15% yield) as a solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.81-8.86 (m, 1H), 8.33-8.40 (m, 1H),7.53-7.59 (m, 1H), 7.27-7.35 (m, 1H), 7.03-7.16 (m, 2H), 6.91-7.00 (m,2H), 5.99-6.05 (m, 2H), 5.39-5.47 (m, 1H), 4.55-4.68 (m, 1H), 3.78-3.89(m, 1H), 1.75-2.06 (m, 5H), 1.46-1.60 (m, 2H), 1.07-1.13 (m, 3H).

Compound I-362

The title compound was prepared following general procedure B, except1-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)ethanone(described in step 1 towards the synthesis of Compound I-451 was used inplace of Intermediate 1,2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropan-2-ol was the aminereactant, and contents were heated to 100° C. for 36 h as a solution indioxane. The resulting crude material was purified via silica gelchromatography utilizing a 0-10% methanol/dichloromethane gradientfollowed by further purification by reverse phase HPLC to deliver thedesired compound, Compound I-362 (7 mg, 14% yield) as an off-whitesolid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 8.54 (s, 1H), 8.36 (d, 1H), 8.07 (br.s., 1H), 7.58-7.69 (m, 1H), 7.33 (q, 1H), 7.16-7.26 (m, 1H), 7.10 (t,1H), 6.92-7.02 (m, 1H), 5.81 (s, 2H), 4.12 (d, 2H), 2.56 (s, 3H).

Compound I-462

The title compound was prepared following general procedure B, except1-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)ethanone(described in step 1 towards the synthesis of Compound I-451 was used inplace of Intermediate 1, 2-aminopropane-1,3-diol was the amine reactant,and contents were heated to 100° C. for 36 h as a solution in dioxane.The resulting crude material was purified via silica gel chromatographyutilizing a 0-10% methanol/dichloromethane gradient followed by furtherpurification by reverse phase HPLC to deliver the desired compound,Compound I-462 (10 mg, 26% yield) as an off-white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 8.18 (d, 1H), 7.65 (d, 1H), 7.33 (q,1H), 7.21 (dd, 2H), 7.10 (t, 1H), 6.79 (t, 1H), 5.82 (s, 2H), 4.72 (t,2H), 4.33 (d, 1H), 3.52-3.64 (m, 4H), 2.57 (s, 3H).

Compound I-463

The title compound was prepared following general procedure B, except1-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)ethanone(described in step 1 towards the synthesis of Compound I-451 was used inplace of Intermediate 1, (2R,3S)-3-methylpiperidine-2-carboxylic acidwas the amine reactant, and contents were heated to 100° C. for 36 h asa solution in dioxane. The crude material was purified via silica gelchromatography utilizing a 0-10% methanol/dichloromethane gradientfollowed by further purification by reverse phase HPLC to deliver thedesired compound, Compound I-463 (6.5 mg, 15% yield) as an off-whitesolid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 8.38 (d, 1H), 7.69 (s, 1H), 7.33 (q,1H), 7.17-7.27 (m, 1H), 7.11 (t, 1H), 6.77-6.89 (m, 1H), 5.82 (s, 2H),4.85 (d, 1H), 4.26-4.28 (m, 1H), 3.48-3.57 (m, 1H), 2.56 (s, 3H),1.98-2.12 (m, 1H), 1.83 (d, 1H), 1.58-1.71 (m, 2H), 1.34-1.47 (m, 1H),1.11 (d, 3H), COOH protons exchanged.

Compound I-519

2-((Tert-butoxycarbonyl)amino)acetic acid (1 equiv.), HATU (1.1 equiv.),and Hunig's Base (1.3 equiv.) was stirred as a solution in DMF at 23° C.for 2 h. Intermediate 2 (1 equiv.) was then added in a single portion,and contents were heated in the microwave at 100° C. for 30 min. Thereaction was quenched by addition of water, extracted with ethylacetate, and the organic extracts were washed with water and brine. Themixture was dried, filtered, concentrated in vacuo, and purified viasilica gel chromatography to deliver the desired compound, CompoundI-519 (60 mg, 53% yield) as a yellow solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.03-11.19 (m, 1H), 9.11 (d, 1H), 8.73(d, 1H), 7.93-8.04 (m, 1H), 7.65 (s, 1H), 7.33 (q, 1H), 7.20-7.29 (m,2H), 7.06-7.16 (m, 2H), 6.89 (t, 1H), 5.92 (s, 2H), 3.83 (d, 2H),1.36-1.42 (m, 9H).

Compound I-520

To a solution of Compound I-519 in dichloromethane at 0° C. was addedtrifluoroacetic acid of equal volume, and contents were allowed to warmto 23° C. over a period of 12 h. Contents were dried in vacuo, and theresulting residue was taken up in saturated NaHCO₃ solution andextracted with a mixture of isopropanol/dichloromethane. Contents weredried, filtered, and concentrated in vacuo to deliver the desiredcompound, Compound I-520 (37 mg, 79% yield) as a brown solid.

¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.10 (d, 1H), 8.74 (d, 1H), 8.04 (d,1H), 7.68 (s, 1H), 7.34 (q, 1H), 7.29 (d, 1H), 7.18-7.26 (m, 1H), 7.11(t, 1H), 6.88 (t, 1H), 5.93 (s, 2H), 3.36 (s, 2H), NH protons wereexchanged.

Compound I-535

To a solution of Compound I-520 (1 equiv.) and triethylamine (2 equiv.)in dichloromethane maintained at 0° C. was added acetyl chloride (1.2equiv.), and the resulting mixture was allowed to warm to 23° C., over aperiod of 18 h. The solvents were removed in vacuo, and the resultingresidue was triturated with a mixture of ethyl acetate/hexanes. Contentswere filtered, and the resulting solid was dried in vacuo to deliver thedesired compound, Compound I-535 (6 mg, 53% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.18 (s, 1H), 9.11 (d, 1H), 8.73 (d,1H), 8.22 (t, 1H), 7.98 (d, 1H), 7.66 (s, 1H), 7.30-7.39 (m, 1H), 7.27(d, 1H), 7.20-7.26 (m, 1H), 7.12 (td, 1H), 6.89 (t, 1H), 5.93 (s, 2H),3.97 (d, 2H), 1.83-1.93 (m, 3H).

Compound I-543

To a solution of Compound I-520 (1 equiv.) and triethylamine (6 equiv.)in dichloromethane maintained at 0° C. was added methanesulfonylchloride (3.3 equiv.), and the resulting mixture was allowed to warm to23° C. over a period of 3 h. The reaction was quenched by addition ofwater, and the mixture was extracted with dichloromethane. Contents weredried, concentrated in vacuo, and purified via silica gel chromatographyto deliver the desired compound, Compound I-543 (6.2 mg, 47% yield) as awhite solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.17 (s, 1H), 9.11 (d, 1H), 8.76 (d,1H), 8.00 (d, 1H), 7.66 (s, 1H), 7.54 (t, 1H), 7.30-7.39 (m, 1H), 7.27(d, 1H), 7.21-7.26 (m, 1H), 7.12 (t, 1H), 6.89 (t, 1H), 5.93 (s, 2H),3.99 (d, 2H), 2.98 (s, 3H).

Compound I-584

To a solution of Compound I-520 (1 equiv.) in dichloromethane was addedisocyanatotrimethylsilane (1.1 equiv.), and the resulting suspension washeated to 40° C. for 18 h. After the reaction was complete, the solventwas removed in vacuo, and the resulting residue was purified via reversephase HPLC to deliver the desired compound, Compound I-584 (16 mg, 55%yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.02 (s, 1H), 9.10 (d, 1H), 8.73 (d,1H), 7.99 (d, 1H), 7.59-7.68 (m, 1H), 7.30-7.37 (m, 1H), 7.19-7.27 (m,2H), 7.12 (t, 1H), 6.89 (t, 1H), 6.25 (t, 1H), 5.93 (s, 2H), 5.72 (s,2H), 3.90 (d, 2H).

Compound I-585

To a solution of Compound I-520 (1 equiv.) in dichloromethane was addedisopropyl isocyanate (1.1 equiv.), and the resulting mixture was heatedto 40° C. for 18 h. After the reaction was complete, the solvents wereremoved in vacuo and the resulting residue was purified via reversephase HPLC to deliver the desired compound, Compound I-585 (19 mg, 59%yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.04 (s, 1H), 9.10 (d, 1H), 8.72 (d,1H), 7.98 (d, 1H), 7.64 (s, 1H), 7.30-7.38 (m, 1H), 7.19-7.28 (m, 2H),7.12 (td, 1H), 6.85-6.95 (m, 1H), 6.09 (d, 1H), 6.01 (t, 1H), 5.92 (s,2H), 3.92 (d, 2H), 3.58-3.71 (m, 1H), 1.03 (d, 6H).

Compound I-586

To a solution of Compound I-520 (1 equiv.) and triethylamine (2 equiv.)in dichloromethane was added dimethylsulfamoyl chloride (1.5 equiv.),and the mixture was heated at 40° C. for 18 h. After the reaction wascomplete, the solvents were removed in vacuo, and the resulting residuewas purified via reverse phase HPLC to deliver the desired compound,Compound I-586 (9 mg, 28% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.12 (s, 1H), 9.10 (d, 1H), 8.75 (d,1H), 8.00 (d, 1H), 7.64 (s, 1H), 7.58 (t, 1H), 7.30-7.38 (m, 1H),7.19-7.27 (m, 2H), 7.12 (td, 1H), 6.90 (t, 1H), 5.92 (s, 2H), 3.92 (d,2H), 2.67 (s, 6H).

Compound I-633

The title compound was prepared following general procedure B, except(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)methanolwas the amine reactant, and the contents were heated to 100° C. for 48 has a solution in THF/dioxane/water (1:10:1). The crude material waspurified via silica gel chromatography utilizing a 0-10%methanol/dichloromethane gradient followed by reverse phase HPLC todeliver the desired compound, Compound I-633 (6 mg, 36% yield) as anoff-white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.11 (d, 1H), 8.46 (d, 1H), 7.67 (s,1H), 7.30-7.38 (m, 1H), 7.28 (d, 1H), 7.19-7.25 (m, 1H), 7.11 (t, 1H),6.85 (t, 1H), 5.88-5.98 (m, 2H), 5.61 (d, 1H), 5.20 (t, 1H), 5.13 (br.s., 1H), 4.82 (d, 1H), 4.38-4.51 (m, 2H), 3.64 (dt, 1H), 3.50-3.59 (m,1H).

Compound I-466

The title compound was prepared following general procedure B, except2,2,2-trifluoroethanamine (as the HCl salt) was the amine reactant, andthe contents were heated to 90-100° C. for 42 h. The crude material waspurified via preparative HPLC utilizing a 25-80% acetonitrile/watergradient (with 0.1% TFA) to deliver the desired compound, Compound I-466(35 mg, 60% yield) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.76 (d, 1H), 8.20 (d, 1H), 7.46 (s, 1H),7.28 (app. q, 1H), 7.10 (m, 1H), 7.03 (app. t, 1H), 6.92 (d, 1H), 6.80(app. t, 1H), 5.97 (s, 2H), 4.44 (q, 2H).

Compound I-487

The title compound was prepared following general procedure B, except2-(methylsulfonyl)ethanamine (as the HCl salt) was the amine reactant,and the contents were heated to 100° C. for 17 h. The contents werecooled to ambient temperature, diluted with water and acidified to pH 3with 1N HCl solution. The resulting precipitate was filtered and driedin vacuo to deliver the desired compound, Compound I-487 (56 mg, 91%yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.10 (d, 1H), 8.24 (d, 1H), 7.93 (br. t,1H), 7.54 (s, 1H), 7.33 (app. q, 1H), 7.22 (m, 1H), 7.18 (d, 1H), 7.11(app. t, 1H), 6.88 (app. t, 1H), 5.89 (s, 2H), 3.87 (dt, 2H), 3.46 (t,2H), 3.06 (s, 3H).

Compound I-502

The title compound was prepared following general procedure B, except(1-aminocyclopropyl)methanol (as the HCl salt) was the amine reactant,and the contents were heated to 100° C. for 6.5 h. The crude materialwas purified via silica gel chromatography utilizing a 15%acetonitrile-methanol (7:1) in dichloromethane gradient to deliver thedesired compound, Compound I-502 (54 mg, 90% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ 9.10 (d, 1H), 8.18 (d, 1H), 8.00 (s, 1H),7.41 (s, 1H), 7.33 (app. q, 1H), 7.24-7.20 (m, 1H), 7.22 (d, 1H), 7.11(app. t, 1H), 6.89 (app. t, 1H), 5.86 (s, 2H), 4.89 (t, 1H), 3.63 (d,2H), 0.85 (m, 2H), 0.77 (m, 2H).

Compound I-581

The title compound was prepared following general procedure B, except3-aminopropanamide (as the HCl salt) was the amine reactant, and thecontents were heated to 100° C. for 21 h. The contents were cooled toambient temperature, diluted with water and acidified to pH 4 with 1NHCl solution. The resulting precipitate was filtered and dried in vacuoto deliver the desired compound, Compound I-581 (66 mg, 89% yield) as awhite solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.08 (d, 1H), 8.17 (d, 1H), 7.65 (t,1H), 7.50 (s, 1H), 7.34 (br. s, 1H), 7.32 (app. q, 1H), 7.24-7.18 (m,1H), 7.21 (d, 1H), 7.10 (app. t, 1H), 6.86 (br. s, 1H), 6.84 (m, 1H),5.90 (s, 2H), 3.67 (dt, 2H), 2.45 (t, 2H).

Compound I-515

A solution of Compound I-358 in dichloromethane was treated withN,N-diisopropylethylamine (2 equiv.) followed byO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 1.5 equiv.). After 1 h, ammonia (0.5Nsolution in dioxane, 3 equiv.) was added and the light brownish orangesolution was stirred for 21 h. The resultant light tan suspension wasdiluted with water and extracted with dichloromethane. The organicphases were dried over sodium sulfate, filtered and the solvent wasremoved in vacuo. The crude material was purified via silica gelchromatography utilizing a 10-15% acetonitrile-methanol (7:1) indichloromethane gradient to deliver the desired compound, Compound I-515(36 mg, 73% yield) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.76 (s, 1H), 8.10 (d, 1H), 7.42 (s, 1H),7.28 (app. q, 1H), 7.10 (m, 1H), 7.05 (app. t, 1H), 6.90 (s, 1H), 6.89(m, 1H), 5.96 (s, 2H), 3.88 (s, 2H), 1.20 (m, 2H), 1.02 (m, 2H).

Compound I-536

A solution of Compound I-86 in dichloromethane was treated withN,N-diisopropylethylamine (2 equiv.) followed by HATU (1.5 equiv.).After 1 h, ammonia (0.5 N solution in dioxane, 3 equiv.) was added andthe reaction was stirred for 24 h. The resultant mixture was dilutedwith water and extracted with dichloromethane. The organic phases weredried over sodium sulfate, filtered and the solvent was removed invacuo. The crude material was purified via silica gel chromatographyutilizing a 10-25% acetonitrile-methanol (7:1) in dichloromethanegradient to deliver the desired compound, Compound I-536 (33 mg, 81%yield) as an off-white solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm 8.47 (d, 1H), 8.15 (d, 1H), 7.28 (s, 1H),7.22 (app. q, 1H), 7.03 (app. t, 1H), 6.99 (app. t, 1H), 6.94 (app. t,1H), 6.61 (d, 1H), 6.56 (br. s, 1H), 5.99 (d, 1H), 5.89 (d, 1H), 5.60(d, 1H), 5.50 (br. s, 1H), 4.57 (app. t, 1H), 2.32 (m, 1H), 1.09 (d,3H), 1.07 (d, 3H).

Compound I-537

A solution of Compound I-69 in dichloromethane was treated withN,N-diisopropylethylamine (2 equiv.) followed by HATU (1.5 equiv.).After 1 h, ammonia (0.5 N solution in dioxane, 3 equiv.) was added andthe reaction was stirred for 24 h. The resultant mixture was dilutedwith water and extracted with dichloromethane. The organic phases weredried over sodium sulfate, filtered and the solvent was removed invacuo. The crude material was purified via silica gel chromatographyutilizing a 10-25% acetonitrile-methanol (7:1) in dichloromethanegradient to deliver the desired compound, Compound I-537 (27 mg, 65%yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.11 (d, 1H), 8.23 (d, 1H), 7.57 (br. s,1H), 7.53 (s, 1H), 7.38-7.30 (m, 2H), 7.24-7.16 (m, 2H), 7.16 (d, 1H),7.10 (app. t, 1H), 6.85 (app. t, 1H), 5.87 (s, 2H), 4.42 (app. t, 1H),2.20 (m, 1H), 0.97 (app. t, 6H).

Compound I-538

A solution of Compound I-85 in dichloromethane was treated withN,N-diisopropylethylamine (2 equiv.) followed by HATU (1.5 equiv.).After 1 h, ammonia (0.5 N solution in dioxane, 3 equiv.) was added andthe reaction was stirred for 24 h. The resultant mixture was dilutedwith water and extracted with dichloromethane. The organic phases weredried over sodium sulfate, filtered and the solvent was removed invacuo. The crude material was purified via silica gel chromatographyutilizing a 10-25% acetonitrile-methanol (7:1) in dichloromethanegradient to deliver the desired compound, Compound I-538 (36 mg, 86%yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.10 (d, 1H), 8.22 (m, 2H), 7.40 (br. s,1H), 7.36-7.28 (m, 2H), 7.23 (m, 1H), 7.15 (s, 1H), 7.11 (app. t, 1H),6.98 (br. s, 1H), 6.86 (app. t, 1H), 5.86 (s, 2H), 1.42 (m, 2H), 1.02(m, 2H).

Compound I-546

A suspension of Compound I-67 in dichloromethane was treated withdi(1H-imidazol-1-yl)methanone (CDI, 3 equiv.) and the resultant mixturewas heated at 45° C. for 1 h 40 min. After cooling to ambienttemperature, methanesulfonamide (5 equiv.) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1 equiv.) were added and thereaction was heated at 45° C. for 1 h. The resultant mixture was cooledto ambient temperature, quenched with 1N HCl solution and extracted withdichloromethane/isopropanol (4:1). The crude solid was dissolved inwater with the aid of 1N NaOH solution and acidified to pH 3-4 bydropwise addition of 1N HCl. The resulting precipitate was filtered anddried in vacuo to deliver the desired compound, Compound I-546 (39 mg,80% yield) as a tan solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 12.1 (s, 1H), 9.11 (d, 1H), 8.27 (d,1H), 8.17 (br. s, 1H), 7.52 (s, 1H), 7.32 (app. q, 1H), 7.22 (m, 1H),7.12 (d, 1H), 7.10 (m, 1H), 6.79 (app. t, 1H), 5.88 (s, 2H), 4.12 (d,2H), 3.17 (s, 3H).

Compound I-566

The title compound was synthesized in 4 steps:

Step 1: Synthesis of 2-((4-methoxybenzyl)oxy)acetic acid

To a solution of (4-methoxyphenyl)methanol (1 equiv.) and 2-bromoaceticacid (1.2 equiv.) in anhydrous THF at 0° C. was added sodium hydride(60% w/w in mineral oil, 3 equiv.) in 3 portions. The mixture wasstirred at 70° C. for 4 h. After cooling to ambient temperature, waterwas added the resultant mixture was washed with hexanes. The aqueousphase was acidified to pH 2 with 1N HCl and extracted with ethylacetate. The organic layer was dried, filtered and the solvent wasremoved in vacuo. Purification via silica gel chromatography with 50%ethyl acetate in hexanes delivered 2-((4-methoxybenzyl)oxy)acetic acid(0.51 g, 71% yield) as a clear solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 7.29 (m, 2H), 6.90 (m, 2H), 4.59 (s, 2H),4.10 (s, 2H), 3.81 (s, 3H).

Step 2: Synthesis of2-((4-methoxybenzyl)oxy)-N-(2,2,2-trifluoroethyl)acetamide

A solution of 2-((4-methoxybenzyl)oxy)acetic acid (1 equiv.) indichloromethane was treated with N,N-diisopropylethylamine (1.5 equiv.)followed by HATU (1.2 equiv.). After 30 min, N,N-diisopropylethylamine(2 equiv.) and 2,2,2-trifluoroethanamine hydrochloride (2 equiv.) wereadded and the reaction was stirred for 17 h. The resultant mixture wasdiluted with water and extracted with dichloromethane. The organicphases were dried over sodium sulfate, filtered and the solvent wasremoved in vacuo. The crude material was purified via silica gelchromatography utilizing a 10-20% ethyl acetate/hexanes gradient todeliver 2-((4-methoxybenzyl)oxy)-N-(2,2,2-trifluoroethyl)acetamide (0.28g, 78% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 7.26 (d, 2H), 6.91 (d, 2H), 6.89 (br. s,1H), 4.52 (s, 2H), 4.02 (s, 2H), 3.93 (dq, 2H), 3.82 (s, 3H).

Step 3: Synthesis ofN-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)-2-((4-methoxybenzyl)oxy)-N-(2,2,2-trifluoroethyl)acetamide

A suspension of3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole(1 equiv.), 2-((4-methoxybenzyl)oxy)-N-(2,2,2-trifluoroethyl)acetamide(1 equiv.) and cesium carbonate (0.8 equiv.) in anhydrous dioxane washeated at 100° C. for 4 d. The resultant mixture was poured intohalf-saturated sodium bicarbonate solution and extracted with ethylacetate. The organic phase was dried over sodium sulfate, filtered andthe solvent was removed in vacuo. The crude material was purified viasilica gel chromatography utilizing a 10-20% ethyl acetate/hexanesgradient to deliverN-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)-2-((4-methoxybenzyl)oxy)-N-(2,2,2-trifluoroethyl)acetamide(16 mg, 12% yield) as a clear oil.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.65 (d, 1H), 8.49 (d, 1H), 7.32 (s, 1H),7.22 (app. q, 1H), 7.07-6.96 (m, 4H), 6.89 (app. t, 1H), 6.73 (d, 2H),6.60 (d, 1H), 6.01 (s, 2H), 4.68 (q, 2H), 4.33 (s, 2H), 4.31 (s, 2H),3.71 (s, 3H).

Step 4: Synthesis of Compound I-566

A biphasic solution ofN-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-pyrimidin-4-yl)-2-((4-methoxybenzyl)oxy)-N-(2,2,2-trifluoroethyl)acetamide(1 equiv.) in dichloromethane/water (10:1) was treated with2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ, 1.2 equiv.) and stirredfor 20 h. Additional amounts of DDQ (2.4 equiv.) were added and thereaction was stirred for 5 d. The reaction mixture was diluted withdichloromethane and filtered. The crude solution was dried over sodiumsulfate, filtered, and the solvent was removed in vacuo. The crudematerial was purified via silica gel chromatography utilizing a 15-50%ethyl acetate/hexanes gradient to deliver the desired compound, CompoundI-566 (2.6 mg, 45% yield) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.78 (d, 1H), 8.55 (d, 1H), 7.44 (s, 1H),7.26 (app. q, 1H), 7.09 (m, 1H), 7.03 (app. t, 1H), 6.87 (d, 1H), 6.80(app. t, 1H), 5.97 (s, 2H), 5.16 (s, 2H), 3.94 (q, 2H).

Compound I-457

The title compound was synthesized in 2 steps:

Step 1: Synthesis of3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazole-5-carbonitrile

A suspension of3-(5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazole-5-carbonitrile(this compound was described in previous patent application publicationWO2013/101830) in phosphoryl trichloride (50 equiv.) as solvent washeated to 65° C. for 2 h 15 min. The reaction mixture was blown driedunder a stream of nitrogen and then concentrated twice from toluene. Theresultant reddish brown oil/solid was dried in vacuo and used in thenext step without further manipulation.

Step 2: Synthesis of Compound I-457

The title compound was prepared following general procedure B, except3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazole-5-carbonitrilewas the chloropyrimidine reactant and(2R,3S)-3-methylpiperidine-2-carboxylic acid was the amine reactant, andthe contents were heated to 100° C. for 18 h. The contents were cooledto ambient temperature, diluted with water, acidified to pH 3 with 1NHCl solution and extracted with dichloromethane. The organic phases weredried over sodium sulfate, filtered and the solvent was removed invacuo. The crude material was purified via reverse phase HPLC utilizinga 25-80% acetonitrile/water gradient (with 0.1% TFA) to deliver thedesired compound, Compound I-457 (18 mg, 38% yield over 2 steps) as awhite solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.32 (d, 1H), 7.65 (s, 1H), 7.41 (app. q,1H), 7.36 (app. t, 1H), 7.23-7.13 (m, 2H), 5.71 (s, 2H), 5.17 (d, 1H),4.48 (br. d, 1H), 3.78 (app. t, 1H), 2.13 (m, 1H), 1.94 (m, 1H), 1.78(m, 2H), 1.54 (m, 1H), 1.22 (d, 3H).

Compound I-474 The title compound was prepared following generalprocedure B, except3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazole-5-carbonitrile(generated in step 1 towards the synthesis of Compound I-457 was used inplace of Intermediate 1,2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropan-2-ol was the aminereactant, and the contents were heated to 100° C. for 16 h. The contentswere cooled to ambient temperature, diluted with water, acidified to pH3 with 1N HCl solution and extracted with dichloromethane. The organicphases were dried over sodium sulfate, filtered and the solvent wasremoved in vacuo. The crude material was purified via reverse phase HPLCutilizing a 25-80% acetonitrile/water gradient (with 0.1% TFA) todeliver the desired compound, Compound I-474 (31 mg, 49% yield over 2steps from3-(5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazole-5-carbonitrile)as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm 8.30 (s, 1H), 7.49 (app. t, 1H), 7.38 (s,1H), 7.35 (app. q, 1H), 7.17 (app. t, 1H), 7.12 (app. t, 1H), 5.65 (br.s, 1H), 5.60 (s, 2H), 4.12 (d, 2H). One of the exchangeable protons wasnot observed.

Compound I-480

The title compound was prepared following general procedure B, except3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazole-5-carbonitrile(generated in step 1 towards the synthesis of Compound I-457 was used inplace of Intermediate 1, and1-(1-carboxycyclopropyl)-N-methylmethanamine (as the HCl salt) was theamine reactant, and the contents were heated to 100° C. for 17 h. Thecontents were cooled to ambient temperature, diluted with water,acidified to pH 3 with 1N HCl solution and extracted withdichloromethane. The organic phases were dried over sodium sulfate,filtered and the solvent was removed in vacuo. The crude material waspurified via preparative HPLC utilizing a 15-70% acetonitrile/watergradient (with 0.1% TFA) to deliver the desired compound, Compound I-480(90 mg, 66% yield over 2 steps from3-(5-fluoro-6-oxo-1,6-dihydropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazole-5-carbonitrile)as an off-white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 12.3 (br. s, 1H), 8.24 (d, 1H), 7.66 (s,1H), 7.44 (app. q, 1H), 7.36 (app. t, 1H), 7.30-7.22 (m, 2H), 5.65 (s,2H), 3.99 (s, 2H), 3.24 (d, 3H), 1.13 (m, 2H), 1.01 (m, 2H).

Compound I-476

A solution of Compound I-474 in 1 N NaOH solution (excess) was heated at65° C. for 70 min. The reaction mixture was cooled to ambienttemperature and acidified to pH 3 with 1N HCl solution. The resultingprecipitate was filtered and dried in vacuo to deliver the desiredcompound, Compound I-476 (13 mg, 77% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 8.50 (s, 1H), 8.34 (d, 1H), 8.03 (br. t,1H), 7.35 (app. q, 1H), 7.32 (s, 1H), 7.22 (m, 1H), 7.13 (app. t, 1H),7.02 (app. t, 1H), 5.87 (s, 2H), 4.13 (d, 2H). The exchangeablecarboxylic acid proton was not observed.

Compound I-481

A suspension of Compound I-480 in water was treated with 1 N NaOHsolution (2 equiv.) and stirred at ambient temperature for 18 h. Thereaction mixture was acidified to pH 3 with 1N HCl solution. Theresulting precipitate was filtered and dried in vacuo to deliver thedesired compound, Compound I-481 (7.4 mg, 64% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 12.3 (br. s, 1H), 8.22 (d, 1H), 8.14(br. s, 1H), 7.60 (br. s, 1H), 7.53 (s, 1H), 7.33 (app. q, 1H), 7.21 (m,1H), 7.12 (app. t, 1H), 6.90 (app. t, 1H), 5.90 (s, 2H), 3.99 (s, 2H),3.24 (d, 3H), 1.14 (m, 2H), 1.02 (m, 2H).

Compound I-327

To a mixture containing 1,2-diethoxycyclobutenedione (1.3 equiv.) andsodium hydride [60% dispersion in mineral oil] (1 equiv.) in THF wasadded Intermediate 2 (1 equiv.). The mixture was stirred at 0° C. for 1h, then removed from the ice bath and allowed to stir at 23° C. for 24h. The mixture was diluted with ethyl acetate and washed with 1N HClsolution. The organic layer was dried over MgSO₄, filtered andevaporated to give a solid. The crude material was purified via silicagel chromatography utilizing a 0-100% ethyl acetate/hexanes gradient todeliver the desired compound, Compound I-327 (90 mg, 43% yield) as alight yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.12 (d, 1H), 8.69 (d, 1H), 7.67 (s,1H), 7.30-7.38 (m, 1H), 7.29 (d, 1H), 7.24 (d, 1H), 7.20 (d, 1H),7.09-7.15 (m, 1H), 6.86-6.92 (m, 1H), 5.92 (s, 2H), 4.81 (q, 2H), 1.36(t, 3H).

Compound I-402

A mixture of Compound I-327 (1 equiv.) and HCl [1.0 M aqueous solution](1 equiv.) in MeOH was heated to 65° C. for 2 h. Upon cooling themixture to 23° C. a yellow precipitate formed, which was collected viafiltration and rinsed with a minimal amount of methanol. The precipitatecollected was dried under vacuum to deliver the desired compound,Compound I-402 (50 mg, 76% yield) as a yellow solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.08-9.17 (m, 1H), 8.64 (d, 1H), 7.73(s, 1H), 7.30-7.42 (m, 1H), 7.28 (s, 1H), 7.17-7.26 (m, 2H), 7.12 (t,1H), 6.90-7.04 (m, 1H), 5.85-6.03 (m, 2H).

Compound I-456

To a cold solution of triethylamine (1.5 equiv.) in dichloromethane at0° C. was added chlorosulfonyl isocyanate (1.5 equiv.). The mixture wasstirred at 0° C. for 30 min. To this mixture was added Intermediate 2 (1equiv.) and tert-butanol (1.5 equiv.), and contents were stirred at 23°C. for 24 h. The mixture was diluted with ethyl acetate and washed withwater. The precipitate was removed by filtration. The organic layer wasdried over MgSO₄, filtered, and concentrated in vacuo to yield a crudeoil, which was purified via silica gel chromatography utilizing a 0-100%ethyl acetate/hexanes gradient to deliver tert-butylN-(2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)sulfamoylcarbamate,the desired Boc-protected sulfamide intermediate. This intermediate wasdissolved in methanol and treated with HCl [a 4.0 M solution in1,4-dioxane] (5 equiv.) and stirred at 23° C. for 24 h. The mixture wasconcentrated in vacuo to deliver the desired compound, Compound I-456(26 mg, 6% yield, HCl salt) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.85 (d, 1H), 8.54 (d, 1H), 7.88 (s, 1H),7.26-7.34 (m, 2H), 7.00-7.14 (m, 4H), 6.05-6.08 (m, 2H).

Compound I-467

The title compound was synthesized in 3 steps:

Step 1: Synthesis of 2-(bromomethyl)-3,3,3-trifluoro-2-hydroxypropanoicacid

A mixture of 2-(bromomethyl)-3,3,3-trifluoro-2-hydroxypropanenitrile (1equiv.), water (1 equiv.) and concentrated sulfuric acid (4 equiv.) washeated to 110° C. in a sealed vial for 1 h. The mixture was poured overice and extracted with diethyl ether. The organic layer was dried overMgSO₄, filtered, and concentrated in vacuo to deliver2-(bromomethyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (1.3 g, 33%yield) as a clear oil.

¹H NMR (500 MHz, CDCl₃) δ ppm 3.89 (d, 1H), 3.63-3.69 (m, 1H).

Step 2: Synthesis of 2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropanoicacid

A mixture of ammonium hydroxide [28% solution in water] (10 equiv.) and2-(bromomethyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (1 equiv.) wasstirred at 23° C. for 24 h. The mixture was concentrated in vacuo. Theresulting solid was treated with a minimal amount of ethanol. Theprecipitate was collected by filtration and dried under vacuum todeliver 2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (412 mg,43% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.86-3.27 (m, 2H).

Step 3: Synthesis of Compound I-467

The title compound was prepared following general procedure B, except2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (4 equiv.) wasthe amine reactant, 6 equivalents of triethylamine was used, andcontents were heated to 85° C. as a solution in 1,4-dioxane/water (4:1)for 24 h. The mixture was cooled to 23° C. and diluted with ethylacetate. The organic layer was washed with saturated solution ofammonium chloride, dried over MgSO₄, filtered, and concentrated in vacuoto yield a crude solid. The crude material was purified via silica gelchromatography utilizing a 0-100% ethyl acetate/hexanes gradient todeliver the desired compound, Compound I-467 (50 mg, 7% yield for step3) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.28 (d, 1H), 7.59 (t, 1H), 7.46 (s,1H), 7.30-7.36 (m, 1H), 7.16-7.24 (m, 2H), 7.10 (t, 1H), 6.91 (t, 1H),5.88 (s, 2H), 4.24 (dd, 1H), 3.84 (dd, 1H).

Compound I-468

A mixture of CDI (6 equiv.) and3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propanoic acid (6 equiv.)in THF was heated to 90° C. for 1 h. To this mixture, was added2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-morpholinopyrimidin-4-amine(this intermediate was described in previously published patentapplication WO2012/3405A1; 1 equiv.). The mixture was stirred at 90° C.for 24 h. The mixture was diluted in ethyl acetate and washed with 1NHCl solution. The organic layer was dried over MgSO₄, filtered andevaporated to give a crude oil. The oil was purified via silica gelchromatography utilizing a 0-100% ethyl acetate/hexanes gradient todeliver the desired compound, Compound I-468 (18 mg, 62%) as a lightyellow solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.76 (d, 1H), 8.64 (s, 1H), 7.60-7.63 (m,1H), 7.20-7.26 (m, 1H), 7.00-7.06 (m, 1H), 6.98 (t, 1H), 6.92 (d, 1H),6.74-6.83 (m, 1H), 5.93 (s, 2H), 3.88-3.92 (m, 4H), 3.04-3.09 (m, 4H).

Compound I-473

To a mixture of5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-pyrimidin-4-amine(this intermediate was described in previously published patentapplication WO2012/3405 A1, 1 equiv.) and3,3,3-trifluoro-2-(trifluoromethyl)-2-((trimethylsilyl)oxy)propanoylchloride (3 equiv.) [prepared according to the procedure described inAicher, T. D. et al. J. Med. Chem. 2000, 43, 245, Method J.] in THF at23° C., was added, very slowly, LiHMDS (2.0 M in THF, 3 equiv.). Theexothermic reaction turned dark brown immediately. The mixture wasstirred at 23° C. for 1 h, then diluted in ethyl acetate and washed with1N HCl solution. The precipitate was removed by filtration. The organiclayer was dried over MgSO₄, filtered, and concentrated in vacuo to givea crude oil. The oil was purified via silica gel chromatographyutilizing a 0-30% ethyl acetate/hexanes gradient to deliver the desiredcompound, Compound I-473 (11 mg, 3% yield) as a yellow solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.83 (d, 1H), 8.80 (s, 1H), 7.60 (s, 1H),7.27-7.33 (m, 1H), 7.09-7.15 (m, 1H), 7.06 (t, 1H), 6.94 (d, 1H), 6.90(t, 1H), 6.00 (s, 2H).

Compound I-477

To a mixture of5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-pyrimidin-4-amine(described in WO2012/3405 A1, 1 equiv.) and morpholine-4-carbonylchloride (1.2 equiv.) in THF at 23° C., was added, very slowly, LiHMDS(2.0 M in THF, 1.2 equiv.). The mixture was stirred at 23° C. for 24 h.The mixture was diluted in ethyl acetate and washed with 1N HClsolution. The organic layer was dried over MgSO₄, filtered andevaporated to give a crude oil. The oil was purified via silica gelchromatography utilizing a 0-5% methanol/DCM gradient to deliver thedesired product, Compound I-477 (24 mg, 18% yield) as a light yellowsolid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.49-8.54 (m, 1H), 7.47 (s, 1H), 7.33-7.42(m, 1H), 7.23-7.30 (m, 1H), 7.12-7.22 (m, 1H), 6.99-7.11 (m, 2H), 6.87(d, 1H), 5.95 (s, 2H), 3.72 (q, 4H), 3.56-3.62 (m, 4H).

Compound I-482

To a cold mixture of triphosgene (0.75 equiv.) and3-bromo-1,1,1-trifluoro-propan-2-ol (1.5 equiv.) in dichloromethane wasadded pyridine (1.5 equiv.). The mixture was stirred at 0° C. for 30min. In a separate flask, a suspension of Intermediate 2 (1 equiv.) inpyridine was cooled to 0° C. To this suspension was transferred themixture of triphosgene and bromopropanol via syringe. The resultingmixture was heated to 60° C. for 24 h. The contents were diluted inethyl acetate and washed with 1N HCl solution. The organic layer wasdried over MgSO₄, filtered and evaporated to give a crude oil. The oilwas purified via silica gel chromatography utilizing a 0-100% ethylacetate/hexanes gradient to deliver the desired compound, Compound I-482(46 mg, 9% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.79 (d, 1H), 8.50 (d, 1H), 8.11-8.14 (m,1H), 7.43 (s, 1H), 7.19-7.27 (m, 1H), 6.96-7.10 (m, 2H), 6.87-6.93 (m,1H), 6.62 (d, 1H), 5.99-6.03 (m, 2H), 4.99-5.07 (m, 1H), 4.57-4.65 (m,1H), 4.49-4.56 (m, 1H).

Compound I-492

A solution of 2,2-bis(trifluoromethyl)-2-hydroxyacetic acid (3 equiv.)and CDI (3 equiv.) in THF was heated to 80° C. for 1 h. To this mixturewas added a solution of5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine(intermediate described in previous WO2012/3405 A1; 1 equiv.) in NMP.The resulting mixture was heated in a microwave to 200° C. for 1 h.Contents were diluted in ethyl acetate and washed with water. Theorganic layer was dried over MgSO₄, filtered, and dried in vacuo to givea crude oil. The oil was purified via silica gel chromatographyutilizing a 0-100% ethyl acetate/hexanes gradient to deliver the desiredproduct, Compound I-492 (25 mg, 8% yield) as a yellow solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.48 (d, 1H), 7.37 (s, 1H), 7.18-7.25 (m,2H), 7.00-7.06 (m, 1H), 6.98 (t, 1H), 6.85 (t, 1H), 6.59 (d, 1H), 5.99(s, 2H).

Compound I-493

A mixture of Compound I-403 (1 equiv.), HOBT (3 equiv.), triethylamine(3 equiv.), HATU (3 equiv.) and cyclopropylamine (3 equiv.) in DMF wasstirred at 23° C. for 24 h. The mixture was diluted with ethyl acetateand washed in sequence with 1N HCl solution, saturated sodiumbicarbonate solution, and brine. The organic layer was dried over MgSO₄,filtered, and concentrated in vacuo to yield a crude oil. The oil waspurified via silica gel chromatography utilizing a 0-100% ethylacetate/hexanes gradient to deliver the desired product, Compound I-493(20.4 mg, 27% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.76-8.80 (m, 1H), 8.25-8.29 (m, 1H),7.47-7.49 (m, 1H), 7.24-7.31 (m, 1H), 7.07-7.14 (m, 1H), 7.03 (t, 1H),6.87-6.90 (m, 1H), 6.77 (t, 1H), 5.95-5.99 (m, 2H), 5.87-5.94 (m, 1H),2.70-2.77 (m, 1H), 0.70-0.78 (m, 2H), 0.47-0.54 (m, 2H).

Compound I-504

The title compound was synthesized in 2 steps:

Step 1: Synthesis of 2-bromo-3,3,3-trifluoropropyl(2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)carbamate

To a cold mixture of triphosgene (0.9 equiv.) and2-bromo-3,3,3-trifluoropropan-1-ol (2 equiv.) in THF was added pyridine(2 equiv.). The mixture was stirred at 0° C. for 30 min. In a separateflask, a suspension of Intermediate 2 (1 equiv.) in pyridine (2 equiv.)was cooled to 0° C. To this suspension was added the mixture oftriphosgene and bromopropanol via syringe, and the resulting mixture washeated to 60° C. for 24 h. Contents were concentrated in vacuo, and theresidue was diluted with ethyl acetate and washed with 1N HCl solution.The organic layer was dried over MgSO₄, filtered, and concentrated invacuo to give a crude oil. The oil was purified via silica gelchromatography utilizing a 0-100% ethyl acetate/hexanes gradient todeliver the desired carbamate intermediate,2-bromo-3,3,3-trifluoropropyl(2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)carbamate (77 mg, 4% yield) as a light brown oil.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.46-8.48 (m, 1H), 8.07 (br. s., 1H), 7.86(d, 1H), 7.44-7.47 (m, 1H), 7.17-7.24 (m, 1H), 7.00-7.07 (m, 1H),6.93-7.00 (m, 1H), 6.78-6.85 (m, 1H), 6.57-6.62 (m, 1H), 6.02 (s, 2H),4.28 (quind, 1H), 3.93-4.15 (m, 2H).

Step 2: Synthesis of Compound I-504

To a solution of 2-bromo-3,3,3-trifluoropropyl(2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)carbamate(1 equiv.) in THF was added LiHMDS (2.0 M in THF, 1 equiv.). The mixturewas sealed and heated to 60° C. for 2 d. The mixture was diluted withethyl acetate and washed with water. The organic layer was dried MgSO₄,filtered, and evaporated to give a crude oil. The oil was purified viasilica gel chromatography utilizing a 0-100% ethyl acetate/hexanesgradient and recrystallized from a diethyl ether-hexanes mixture todeliver the desired product, Compound I-504 (7 mg, 11% yield) as a whitesolid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.13 (s, 1H), 8.84 (s, 1H), 7.99 (d,1H), 7.70 (s, 1H), 7.31-7.38 (m, 1H), 7.19-7.26 (m, 2H), 7.12 (t, 1H),6.91 (t, 1H), 6.03-6.09 (m, 1H), 5.86-5.98 (m, 2H), 4.73-4.80 (m, 2H).

Compound I-544

A mixture of Compound I-419 (1 equiv.) and lithium aluminum hydride (2equiv.) in THF was heated to 60° C. for 24 h. The mixture was cooled to23° C., then sequentially treated with water (x mL/x g of lithiumaluminum hydride), 15% NaOH (aq) (x mL/x g of lithium aluminum hydride),and water (3×mL/x g of lithium aluminum hydride). The precipitate wasremoved by filtration, and the filtrate was concentrated in vacuo toyield the intermediate amine as a yellow solid. The intermediate wassuspended in THF, and a solution of methanesulfonyl chloride (1 M inTHF, 2 equiv.) and pyridine (3 equiv.) in THF was added to thesuspension dropwise via syringe. The mixture was stirred at 23° C. for 3h, then diluted in ethyl acetate and washed with 1N HCl solution. Theorganic layer was dried, filtered, and evaporated to yield a crude oil.The oil was purified via silica gel chromatography utilizing a 0-100%ethyl acetate/hexanes gradient to deliver the desired product, CompoundI-544 (4 mg, 19% yield) as a yellow solid.

¹H NMR (400 MHz, CD₃OD) δ ppm 8.71-8.78 (m, 1H), 8.22 (d, 1H), 7.51 (s,1H), 7.22-7.32 (m, 1H), 6.97-7.15 (m, 2H), 6.89-6.96 (m, 1H), 6.69-6.83(m, 1H), 5.99-6.05 (m, 2H), 5.56 (s, 1H), 3.03-3.23 (m, 2H), 2.68-2.83(s, 3H), 1.95-2.08 (m, 2H).

Compound I-575

The title compound was synthesized in 3 steps:

Step 1: Synthesis of(R)-1-((tert-butyldimethylsilyl)oxy)-3-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)propan-2-ol

A mixture of Compound I-316 (1 equiv.), imidazole (2 equiv.) andTBDMS-Cl (1 equiv.) in DMF was stirred at rt for 24 h. The mixture wasdiluted in ethyl acetate and washed with 1N HCl solution. The organiclayer was dried, filtered and evaporated to give a crude oil. The oilwas purified via silica gel chromatography utilizing a 0-100% ethylacetate/hexanes gradient to deliver the desired intermediate,(R)-1-((tert-butyldimethylsilyl)oxy)-3-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)propan-2-ol(258 mg, 63% yield).

¹H NMR (500 MHz, CDCl₃) δ ppm 8.34 (d, 1H), 8.04-8.07 (m, 1H), 7.23 (br.s., 1H), 7.06-7.13 (m, 1H), 6.82-6.97 (m, 3H), 6.76 (t, 1H), 5.84-5.90(m, 2H), 3.80-3.89 (m, 1H), 3.47-3.66 (m, 4H), 0.79-0.84 (m, 9H), 0.03(m, 6H).

Step 2: Synthesis of(R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)oxazolidin-2-one

A mixture of(R)-1-((tert-butyldimethylsilyl)oxy)-3-((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)propan-2-ol(1 equiv.), 2,6-dimethylpyridine (2 equiv.) and triphosgene (0.7 equiv.)in THF was stirred at 23° C. for 30 min. Then, the mixture was heated to60° C. for 24 h. Contents were diluted in ethyl acetate and washed withwater. The organic layer was dried, filtered and evaporated to give acrude oil. The oil was purified via silica gel chromatography utilizinga 0-100% ethyl acetate/hexanes gradient to deliver the desiredTBS-protected carbamate intermediate,(R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)oxazolidin-2-one(221 mg, 82% yield).

¹H NMR (500 MHz, CDCl₃) δ ppm 8.54 (d, 1H), 8.36 (d, 1H), 7.24 (s, 1H),7.05-7.13 (m, 1H), 6.84-6.97 (m, 2H), 6.72-6.81 (m, 1H), 6.47 (d, 1H),5.87 (s, 2H), 4.65-4.74 (m, 1H), 4.24-4.32 (m, 1H), 4.16 (dd, 1H), 3.83(m, 2H), 0.74-0.82 (m, 9H), 0.00 (d, 6H).

Step 3: Synthesis of Compound I-575

To a cold solution of(R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-(5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)oxazolidin-2-one(1 equiv.) in THF at 25° C., was added a solution of TBAF (1M in THF, 1equiv.). After stirring the mixture at 23° C. for 30 min, the mixturewas quenched with water and diluted with ethyl acetate. The organiclayer was dried, filtered and evaporated to give a crude oil. The oilwas purified via silica gel chromatography utilizing a 0-100% ethylacetate/hexanes gradient. Further purification by recrystallization froma dichloromethane-diethyl ether mixture gave the desired compound,Compound I-575 (10 mg, 4% yield over 3 steps) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.25 (d, 1H), 8.02 (t, 1H), 7.53 (s,1H), 7.30-7.39 (m, 1H), 7.17-7.25 (m, 2H), 7.11 (td, 1H), 6.85-6.91 (m,1H), 5.88 (s, 2H), 5.06 (dq, 1H), 4.61 (t, 1H), 4.45 (dd, 1H), 3.83 (m,2H).

Compound I-490

A mixture of 4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoic acid(1.5 equiv.) and CDI (1.5 equiv.) in THF was heated to reflux for 2 h.To this mixture was added Intermediate 2 (1 equiv.) in one portion. Themixture was diluted in ethyl acetate and washed with 1N HCl solution.The organic layer was dried, filtered, and evaporated to yield an oil.The oil was purified by silica gel chromatography utilizing a 80%isocratic gradient of ethyl acetate in hexanes to deliver the desiredproduct, Compound I-490 (2 mg, 1.2% yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm 8.80 (d, 1H), 8.51 (s, 1H), 8.05 (d, 1H),7.44-7.50 (m, 1H), 7.19-7.32 (m, 2H), 6.95-7.08 (m, 2H), 6.87 (d, 1H),6.58-6.65 (m, 1H), 5.97 (s, 2H), 2.93-2.99 (m, 2H).

Compound I-496

The title compound was prepared following general procedure B, except(5-methyl-1,3,4-oxadiazol-2-yl)methanamine (as the HCl salt) was theamine reactant, and the contents were heated to 110° C. for 24 h as asolution in THF/water (10:1). The contents were cooled to 23° C., andorganic solvents were removed in vacuo. The resulting residue waspurified by reverse phase HPLC to deliver the desired product, CompoundI-496 (81 mg, 64% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.09-9.12 (m, 1H), 8.57 (br. s., 1H),8.32 (d, 1H), 7.48 (s, 1H), 7.30-7.36 (m, 1H), 7.19-7.25 (m, 1H), 7.16(d, 1H), 7.11 (t, 1H), 6.84 (t, 1H), 5.88 (s, 2H), 4.92 (d, 2H), 2.45(s, 3H).

Compound I-508

The title compound was prepared in 3 steps:

Step 1: Synthesis of tert-butyl(1-(cyclopropylamino)-3-methyl-1-oxobutan-2-yl)carbamate

To a solution of 2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (1eq) and cyclopropanamine (1 eq) in THF (10 ml) were added PyAOP (1.0 eq)followed by DIPEA (3 eq). Reaction mixture was stirred at roomtemperature for 4 hours. With complete conversion of starting materialto the desired product, the solvent was removed by vacuum and purifiedby flash chromatography eluent with ethyl acetate/hexane 1:1 Thefractions containing desired product were collected and concentrated toprovide the amide intermediate as an oil.

Step 2: Synthesis of 2-amino-N-cyclopropyl-3-methylbutanamide

The amide intermediate tert-butyl(1-(cyclopropylamino)-3-methyl-1-oxobutan-2-yl)carbamate (1 equiv.) wasdissolved in dichloromethane and TFA (3:1 ratio) and stirred for 4 h at23° C. The solvent was removed in vacuo to yield the free amineintermediate 2-amino-N-cyclopropyl-3-methylbutanamide (0.25 g 42% yield)as a semi-solid.

Step 3: Synthesis of Compound I-508

The title compound was prepared following general procedure B, except2-amino-N-cyclopropyl-3-methylbutanamide was the amine intermediate, andthe contents were heated to 110° C. for 24 h as a solution in THF/water(10:1). The contents were cooled to 23° C., and organic solvents wereremoved in vacuo. The resulting residue was purified via reverse phaseHPLC to deliver the desired product, Compound I-508 (15 mg, 22% yield)as a white solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.51-8.55 (m, 1H), 8.15 (d, 1H), 7.40-7.45(m, 1H), 7.23-7.28 (m, 1H), 6.99-7.12 (m, 2H), 6.70-6.75 (m, 1H),6.62-6.69 (m, 1H), 6.65 (br. s., 1H), 5.93-5.98 (m, 2H), 4.58 (t, 1H),2.75 (tq, 1H), 2.31 (dq, 1H), 0.99-1.08 (m, 6H), 0.67-0.79 (m, 2H),0.44-0.55 (m, 2H).

Compound I-509

The title compound was prepared following general procedure B, except2-((trifluoromethyl)thio)ethanamine was the amine reactant, and thecontents were heated to 110° C. for 24 h as a solution in THF/water(10:1). The contents were cooled to 23° C., and organic solvents wereremoved in vacuo. The resulting residue was purified utilizing a 5-50%ethyl acetate in hexane gradient to deliver the desired product,Compound I-509 (81 mg, 60% yield) as an off-white solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.45-8.48 (m, 1H), 8.20 (d, 1H), 7.30 (s,2H), 7.16-7.23 (m, 1H), 7.00-7.06 (m, 1H), 6.97 (t, 1H), 6.86 (t, 1H),6.57-6.60 (m, 1H), 5.95-6.01 (m, 2H), 3.96 (q, 2H), 3.27 (t, 2H).

Compound I-514

To a stirred solution of Compound I-509 (1 equiv.) in dichloromethanewas added mCPBA (2 equiv.), and the mixture was stirred for 12 h.Solvent was removed in vacuo, and the resulting residue was purified viareverse phase HPLC to deliver the desired product, Compound I-514 (5 mg,6% yield) as a white solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.41 (d, 1H), 8.17 (d, 1H), 7.28-7.32 (m,1H), 7.10-7.17 (m, 1H), 6.89-6.99 (m, 2H), 6.80-6.86 (m, 1H), 6.53 (d,1H), 5.99 (d, 1H), 5.90 (s, 2H), 4.20 (q, 2H), 3.70 (t, 2H).

Compound I-529

The title compound was prepared following general procedure B, except1,1,1,3,3,3-hexafluoro-2-((methylamino)methyl)propan-2-ol was the aminereactant, and the contents were heated to 110° C. for 24 h as a solutionin THF/water (10:1). The contents were cooled to 23° C., and organicsolvents were removed in vacuo. The resulting residue was purified viareverse phase HPLC to deliver the desired product, Compound I-529 (2.5mg, 2% yield) as an off-white solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.53 (d, 1H), 8.36 (d, 1H), 7.42 (br. s.,1H), 7.23-7.28 (m, 2H), 7.03-7.25 (m. 2H), 6.64 (s, 1H), 5.95 (s, 2H),4.22 (br. s., 1H), 3.49-3.53 (m, 3H), 3.02-3.08 br. 2H).

Compound I-545

The title compound was prepared following general procedure B, except(1-(methylsulfonyl)cyclopropyl)methanamine (as the HCl salt) was theamine reactant, and the contents were heated to 110° C. for 24 h as asolution in dioxane/water (10:1). The contents were cooled to 23° C.,and organic solvents were removed in vacuo. The resulting residue waspurified via reverse phase HPLC to deliver the desired product, CompoundI-545 (81 mg, 59% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.12 (d, 1H), 8.30 (d, 1H), 8.19 (br.s., 1H), 7.55-7.61 (m, 1H), 7.31-7.38 (m, 1H), 7.19-7.26 (m, 2H), 7.13(t, 1H), 6.96 (t, 1H), 5.89 (s, 2H), 4.04 (d, 2H), 3.09 (s, 3H), 1.22(s, 4H).

Compound I-567

The title compound was prepared in 5 steps:

Step 1: Synthesis of methyl1-(((tert-butoxycarbonyl)amino)methyl)cyclopropanecarboxylate

To a stirred solution of1-(((tert-butoxycarbonyl)amino)methyl)cyclopropanecarboxylic acid (1equiv.) in diethyl ether and methanol (5:1 ratio) was slowly added(diazomethyl)trimethylsilane (1 equiv.) at 25° C. The mixture wasstirred overnight, and solvents were removed in vacuo to yield thedesired methyl ester intermediate, methyl 1-(((tert-butoxycarbonyl)amino)methyl)cyclopropanecarboxylate (0.400 g, 75% yield).

Step 2: Synthesis of tert-butyl((1-(hydroxymethyl)cyclopropyl)methyl)carbamate

Methyl 1-(((tert-butoxycarbonyl)amino)methyl)cyclopropanecarboxylate (1equiv.) was dissolved in THF and cooled to 0° C. Lithium aluminumhydride (3 equiv.) was added slowly to the vessel, and contents werestirred while allowing warming up to 23° C. over a period of 4 h. Thereaction solution was then re-cooled to 0° C., then water (x mL ofwater/x g of LiAlH₄ used), 15% sodium hydroxide solution (x mL ofwater/x g of LiAlH₄ used), and water (3×mL of water/x g of LiAlH₄ used)were slowly added to the reaction in a sequential manner. The reactionwas filtered through celite, and the filtrate was concentrated in vacuo.The residue was purified via silica gel chromatography to deliver thedesired alcohol intermediate, tert-butyl((1-(hydroxymethyl)cyclopropyl)methyl)carbamate (0.41 g, 88% yield).

Step 3: Synthesis of tert-butyl ((1-formylcyclopropyl)methyl)carbamate

To a solution of tert-butyl((1-(hydroxymethyl)cyclopropyl)methyl)carbamate (1 equiv.) indichloromethane at 25° C. was added PCC (1.15 equiv.) in a singleportion. Reaction was stirred for 2 h. Diethyl ether was added to thevessel, and the heterogeneous mixture was filtered through silica gel toyield the desired aldehyde intermediate, which was used without furtherpurification.

Step 4: Synthesis of (1-(1H-imidazol-2-yl)cyclopropyl)methanamine

A stirred solution of tert-butyl ((1-formylcyclopropyl)methyl)carbamate(1 equiv.) in methanol was treated with ammonium hydroxide (10 equiv.)followed by oxalaldehyde (1.1 equiv.). The contents were allowed to stirat 23° C. for 3 h before methanol was removed in vacuo. The residue wasthen treated with TFA in dichloromethane (1:1 ratio) and stirred at 23°C. for 5 h. The mixture was diluted with brine and extracted withdichloromethane. The organics were dried over sodium sulfate andconcentrated in vacuo to deliver the desired imidazole intermediate,(1-(1H-imidazol-2-yl)cyclopropyl)methanamine (0.124 g, 100% yield),which was carried onto the next reaction without further purification.

Step 4: Synthesis of Compound I-567

The title compound was prepared following general procedure B, except(1-(1H-imidazol-2-yl)cyclopropyl)methanamine was the amine reactant, andthe contents were heated to 110° C. for 24 h as a solution indioxane/water (10:1). The contents were cooled to 23° C., and organicsolvents were removed in vacuo. The residue was purified via reversephase HPLC to deliver the desired product, Compound I-567 (36 mg, 27%yield) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 9.16 (br. s., 1H), 8.53 (d, 1H), 7.98-8.05(m, 1H), 7.51 (s, 1H), 7.22-7.31 (m, 2H), 6.97-7.09 (m, 2H), 6.90 (s,2H), 6.81 (d, 2H), 5.92 (s, 2H), 4.05 (d, 2H), 1.40-1.47 (m, 2H),1.32-1.39 (m, 2H).

Compound I-589

A solution of5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine(intermediate described in previous patent: WO2012/3405 A1) (1 equiv.),2-(methylsulfonyl)propanoic acid (3 equiv.), triethylamine (10 equiv.),and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (4equiv.) in DMF was heated to 90° C. for 4 h. The reaction was cooled to23° C., then poured into a 1:1 mixture of ethyl acetate and water. Thelayers were separated and the aqueous layer was extracted with ethylacetate (2×). The organics were washed with water (3×), dried overmagnesium sulfate, filtered, and concentrated in vacuo. The resultingresidue was purified via reverse phase HPLC to deliver the desiredproduct, Compound I-589 (10 mg, 28% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.49 (s, 1H), 9.11 (d, 1H), 8.92 (d,1H), 7.61 (s, 1H), 7.31-7.37 (m, 1H), 7.27 (d, 1H), 7.19-7.25 (m, 1H),7.12 (td, 1H), 6.92-6.97 (m, 1H), 5.92 (s, 2H), 4.40 (d, 1H), 3.07 (s,3H), 1.58 (d, 3H).

Compound I-608

The title compound was prepared in 4 steps:

Step 1: Synthesis of tert-butyl (2-hydrazinyl-2-oxoethyl)carbamate

To a solution of methyl 2-((tert-butoxycarbonyl)amino)acetate (1 equiv.)in ethanol was added hydrazine hydrate (15 equiv.), and the reaction wasallowed to stir overnight. The solvent was removed in vacuo, and theresidue was triturated with hexane, filtered, and dried under highvacuum to yield the desired acyl hydrazine intermediate tert-butyl(2-hydrazinyl-2-oxoethyl)carbamate, intermediate B (0.89 g, 92% yield)as a white solid.

Step 2: Synthesis of tert-butyl(2-oxo-2-(2-(2,2,2-trifluoroacetyl)hydrazinyl)ethyl)carbamate

To a solution of tert-butyl (2-hydrazinyl-2-oxoethyl)carbamate (1equiv.) in acetonitrile was added DIEA (1.1 equiv.). Contents werecooled to −45° C., and 2,2,2-trifluoroacetic anhydride (1.1 equiv.) wasadded to the reaction. The resulting mixture was stirred while slowlywarming to 23° C. The solvent was removed in vacuo and the residue waspartitioned between water and ethyl acetate. The layers were separated,and the aqueous layer was extracted with ethyl acetate. The combinedorganic phases were washed with water and brine, dried with Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified via silicagel chromatography, utilizing a 5-45% ethyl acetate in hexanes gradientto deliver the desired intermediate, tert-butyl(2-oxo-2-(2-(2,2,2-trifluoroacetyl)hydrazinyl)ethyl)carbamate (0.73 g,54% yield).

Step 3: Synthesis of(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)methanamine

To a suspension of tert-butyl(2-oxo-2-(2-(2,2,2-trifluoroacetyl)hydrazinyl)ethyl)carbamate (1 equiv.)in acetonitrile was added DIEA (5.8 equiv.) and triphenylphosphine (4.1equiv.), which was stirred for 5 min. Perchloroethane (2.3 equiv.) wasthen added to the reaction, and the mixture was stirred for 20 h at 23°C. The solvent was removed in vacuo, and the residue was partitionedbetween water and ethyl acetate. The layers were separated, and theaqueous layer was extracted with ethyl acetate. The combined organicphases were washed with water and brine, dried with Na₂SO₄, filtered,and concentrated in vacuo. The residue was purified via silica gelchromatography, utilizing a 5-45% ethyl acetate in hexanes gradient todeliver the N-Boc protected oxadiazole intermediate, tert-butyl((5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)methyl)carbamate (0.24 g, 35%yield). To a stirred solution of this N-Boc protected oxadiazoleintermediate (1 equiv.) in dichloromethane was added TFA (8 equiv.), andthe mixture was stirred at 23° C. for 4 h. The solvent was removed invacuo to deliver the desired free amine oxadiazole intermediate,(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)methanamine (as the HCl salt,0.15 g, 100% yield), which was used in the next step without furtherpurification.

Step 4: Synthesis of Compound I-608

To a stirred solution of(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)methanamine (as the HCl salt,2 equiv.) in dioxane cooled to 0° C. was added cesium carbonate (3equiv.), and the mixture was stirred for 1 h. Intermediate 1 (1 equiv.)was added to the reaction, and the resulting mixture was stirred at 90°C. for 24 h. The reaction was cooled to 23° C. and diluted with ethylacetate. The organics were washed with water and brine, concentrated invacuo, and the resulting residue was purified via reverse phase HPLC todeliver the desired product, Compound I-608 (2.5 mg, 5% yield) as awhite solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.67 (d, 1H), 8.15 (d, 1H), 7.31 (s, 1H),7.17 (ddd, 1H), 6.96-7.01 (m, 1H), 6.90-6.95 (m, 1H), 6.76 (d, 1H),6.70-6.74 (m, 1H), 5.85 (s, 2H), 5.09 (s, 2H).

Compound I-622

The title compound was prepared in 4 steps:

Step 1: Synthesis of (R)-tert-butyl(1-hydrazinyl-1-oxopropan-2-yl)carbamate

The title compound was prepared according to the procedure described inStep 1 towards the synthesis of Compound I-608, except using (R)-methyl2-((tert-butoxycarbonyl)amino)propanoate as the starting material (97%yield).

Step 2: Synthesis of (R)-tert-butyl(1-oxo-1-(2-(2,2,2-trifluoroacetyl)hydrazinyl) propan-2-yl)carbamate

This was prepared according to the procedure described in Step 2 towardsthe synthesis of Compound I-608, except using (R)-tert-butyl(1-hydrazinyl-1-oxopropan-2-yl)carbamate as the starting material (82%yield).

Step 3: Synthesis of(R)-1-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)ethanamine

This was prepared according to the procedure described in Step 3 towardsthe synthesis of Compound I-608, except using(R)-tert-butyl(1-oxo-1-(2-(2,2,2-trifluoroacetyl)hydrazinyl)propan-2-yl)-carbamate as the starting material (37% yield).

Step 4: Synthesis of Compound I-622

To a stirred solution of(R)-1-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)ethanamine,(R)-1-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)ethanamine (2 equiv.)and Intermediate 1 (1 equiv.) in DMF was added cesium carbonate (3equiv.). The mixture was heated to 90° C. and stirred for 24 h. Contentscooled to 23° C. and diluted with ethyl acetate. The mixture was washedwith water and brine, concentrated in vacuo, and the resulting residuewas purified via reverse phase HPLC to deliver the desired product,Compound I-622 (5 mg, 9% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.66-8.69 (m, 1H), 8.14 (d, 1H), 7.27 (s,1H), 7.15-7.21 (m, 1H), 6.99 (dd, 1H), 6.93 (t, 1H), 6.76 (d, 1H), 6.72(t, 1H), 5.87-5.91 (m, 1H), 5.85 (s, 2H), 1.74 (d, 3H).

Compound I-616

To a stirred solution of 2-(methylsulfonyl)acetamide (1 equiv.) in DMFwas added cesium carbonate (3 equiv.) at 0° C., and the mixture wasstirred for 1 h. Intermediate 1 (1 equiv.) was added to the vessel, andthe reaction was heated to 90° C. and stirred for 24 h. Contents werecooled to 23° C., and diluted with ethyl acetate. The mixture was washedwith water and brine, concentrated in vacuo, and the resulting residuewas purified via reverse phase HPLC to deliver the desired product,Compound I-616 (11 mg, 22% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.67 (d, 1H), 8.59 (d, 1H), 7.45 (s, 1H),7.17 (ddd, 1H), 6.91-7.02 (m, 2H), 6.77-6.82 (m, 2H), 5.87 (s, 2H), 4.58(br. s., 2H), 3.11 (s, 3H).

Compound I-386

The title compound was prepared following general procedure C, except1H-pyrazole-3-carboxylic acid was the acid reactant, and the crudematerial was purified via silica gel chromatography utilizing a 3-8%methanol in dichloromethane gradient to deliver the desired compound,Compound I-386 (20.2 mg, 40% yield) as a light-tan solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm 9.93 (s, 1H), 8.77 (d, 1H), 8.50 (s, 1H),8.33 (d, 1H), 7.51 (s, 1H), 7.44 (d, 1H), 7.19-7.25 (m, 1H), 7.02-7.08(m, 1H), 6.96-7.02 (m, 1H), 6.94 (d, 1H), 6.83-6.87 (m, 1H), 6.65 (s,1H), 6.02 (s, 2H); 1 N—H proton not observed.

Compound I-164

To a solution of Intermediate 2 (1 equiv.) in dichloromethane was addedtrifluoroacetic anhydride (3 equiv.) followed by triethylamine (3equiv.). The reaction was heated to 60° C. for 20 min, after which thereaction was concentrated in vacuo. The crude material was purified viasilica gel chromatography utilizing a 1-3% methanol in dichloromethanegradient to deliver the desired compound, Compound I-635 (16.4 mg, 32%yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.95 (br. s, 1H), 8.86 (d, 1H), 8.49 (d, 1H),8.10 (d, 1H), 7.49 (s, 1H), 7.20-7.26 (m, 1H), 7.03-7.07 (m, 1H),6.98-7.02 (m, 1H), 6.82-6.87 (m, 1H), 6.62 (d, 1H), 6.04 (s, 2H).

Compound I-458

The title compound was prepared following general procedure C, except3-hydroxy-5-oxocyclohex-3-enecarboxylic acid (1.3 equiv.) was the acidreactant, and 2.5 equivalents of T3P was used. The crude material waspurified via silica gel chromatography utilizing a 3-10% methanol indichloromethane gradient to deliver the desired compound, Compound I-458(26.4 mg, 30% yield) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.79 (m, 1H), 8.68 (d, 1H), 8.13 (d, 1H), 7.53(s, 1H), 7.24-7.33 (m, 1H), 7.08-7.13 (m, 1H), 7.01-7.08 (m, 1H),6.86-6.92 (m, 2H, 2 shifts isochronous), 5.97 (s, 2H), 2.66-2.75 (m,2H), 2.56-2.64 (m, 2H); 1 C—H proton not observed (isochronous withsolvent peak).

Compound I-459

The title compound was prepared following general procedure C, except5-oxopyrrolidine-2-carboxylic acid (1.2 equiv.) was the acid reactant,and 2.5 equivalents of T3P was used. The crude material was purified viasilica gel chromatography utilizing a 3-10% methanol in dichloromethanegradient, followed by a second purification via silica gelchromatography utilizing a 7-12% (7:1 methanol/acetonitrile) indichloromethane gradient to deliver the desired compound, Compound I-459(12.6 mg, 15% yield) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.79 (s, 1H), 8.70 (d, 1H), 8.13 (d, 1H), 7.52(s, 1H), 7.26-7.32 (m, 1H), 7.08-7.13 (m, 1H), 7.02-7.08 (m, 1H),6.87-6.93 (m, 2H, 2 shifts isochronous), 5.95 (s, 2H), 4.41-4.49 (m,1H), 2.52-2.60 (m, 1H), 2.40-2.50 (m, 1H), 2.32-2.40 (m, 1H), 2.20-2.30(m, 1H).

Compound I-464

The title compound was prepared following general procedure C, except5-oxopyrrolidine-3-carboxylic acid (1.2 equiv.) was the acid reactant,and 2.5 equivalents of T3P was used. The crude material was purified viasilica gel chromatography utilizing a 3-10% methanol in dichloromethanegradient to deliver the desired compound, Compound I-464 (31.3 mg, 31%yield) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.79 (s, 1H), 8.69 (d, 1H), 8.13 (d, 1H), 7.51(s, 1H), 7.26-7.31 (m, 1H), 7.07-7.13 (m, 1H), 7.02-7.07 (m, 1H),6.86-6.93 (m, 2H, 2 shifts isochronous), 5.97 (s, 2H), 3.67-3.76 (m,1H), 3.57-3.65 (m, 2H), 2.60-2.72 (m, 2H).

Compound I-461

The title compound was prepared following general procedure C, except1-(benzyloxy)cyclopropanecarboxylic acid (1 equiv.) was the acidreactant, and 2.5 equivalents of T3P was used. The crude material waspurified via silica gel chromatography utilizing a 30-50% ethyl acetatein hexanes gradient to deliver the desired compound, Compound I-461(14.2 mg, 19% yield) as a tan solid.

¹H-NMR (500 MHz, CDCl₃) δ 9.33 (s, 1H), 8.73 (d, 1H), 8.48 (d, 1H), 8.08(d, 1H), 7.42 (s, 1H), 7.34-7.41 (m, 4H), 7.29-7.32 (m, 1H), 7.18-7.23(m, 1H), 7.02-7.06 (m, 1H), 6.97-7.01 (m, 1H), 6.84-6.88 (m, 1H), 6.61(d, 1H), 6.03 (s, 2H), 4.68 (s, 2H), 1.45-1.51 (m, 2H), 1.32-1.37 (m,2H).

Compound I-469

The title compound was prepared following general procedure C, except2-(thiazol-2-yl)acetic acid was the acid reactant. The crude materialwas purified via silica gel chromatography utilizing a 3-8% methanol indichloromethane gradient, followed by a second purification via reversephase HPLC utilizing a 10-95% acetonitrile in water gradient to deliverthe desired compound, Compound I-469 (4.3 mg, 6% yield) as a tan solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.81 (s, 1H), 8.69 (d, 1H), 8.20 (d, 1H), 7.81(d, 1H), 7.61 (d, 1H), 7.57 (s, 1H), 7.25-7.33 (m, 1H), 7.08-7.13 (m,1H), 7.02-7.07 (m, 1H), 6.87-6.96 (m, 2H, 2 shifts isochronous), 5.99(s, 2H), 3.30 (s, 2H).

Compound I-465

To a solution of5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-pyrimidin-4-amine(intermediate described in WO2012/3405 A1; 1 equiv.) in dichloromethanewas added trifluoroacetic anhydride (3 equiv.) followed by triethylamine(3 equiv.). The reaction was heated to 60° C. for 20 min, after whichthe reaction was concentrated in vacuo. The crude material was purifiedvia silica gel chromatography utilizing a 1-3% methanol indichloromethane gradient to deliver the desired compound, Compound I-465(26.8 mg, 28% yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.77 (s, 1H), 8.56 (br. s, 1H), 8.40 (s, 1H),7.44 (s, 1H), 7.19-7.25 (m, 1H), 7.02-7.08 (m, 1H), 6.96-7.02 (m, 1H),6.81-6.88 (m, 1H), 6.62 (d, 1H), 6.02 (s, 2H).

Compound I-470

To a mixture of Compound I-38 (1 equiv.),1-hydroxycyclopropanecarboxylic acid (1.1 equiv.), and 4-dimethylaminopyridine (0.1 equiv.) in dichloromethane was added triethylamine (3equiv.) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.1equiv.). The reaction was stirred at room temperature for 12 h, afterwhich the reaction was diluted with water and 1N hydrochloric acidsolution and extracted with dichloromethane. The combined organic layerswere dried over sodium sulfate, filtered, and concentrated in vacuo. Thecrude material was purified via reverse phase HPLC utilizing a 10-95%acetonitrile in water gradient to deliver the desired compound, CompoundI-470 (1.3 mg, 4% yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.50 (d, 1H), 8.26 (s, 1H), 7.33 (s, 1H),7.19-7.26 (m, 1H), 6.97-7.07 (m, 3H), 6.67 (m, 1H), 5.93 (s, 2H), 5.31(m, 1H), 4.91-5.04 (m, 2H), 4.42-4.75 (m, 2H), 4.16-4.32 (m, 1H),1.28-1.43 (m, 2H), 0.79-0.92 (m, 2H); 1 exchangeable proton notobserved.

Compound I-471 The title compound was prepared following generalprocedure C, except 3,3,3-trifluoropropanoic acid was the acid reactant,2.5 equivalents of T3P was used, and the reaction was stirred at 23° C.for 24 h. The crude material was purified via silica gel chromatographyutilizing a 3-10% methanol in dichloromethane gradient to deliver thedesired compound, Compound I-471 (79.3 mg, 85% yield) as a tan solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.78 (d, 1H), 8.48 (d, 1H), 8.47 (br. s, 1H),8.09 (d, 1H), 8.03 (s, 1H), 7.47 (s, 1H), 7.19-7.24 (m, 1H), 7.02-7.09(m, 1H), 6.96-7.01 (m, 1H), 6.81-6.86 (m, 1H), 6.61 (d, 1H), 6.03 (s,1H), 3.29 (q, 2H).

Compound I-472

To a solution of Intermediate 2 (1 equiv.) in dichloromethane was addedmethylsulfonylmethylsulfonyl chloride (1.08 equiv.) followed by1,8-diazabicyclo[5.4.0]undec-7-ene (1 equiv.). The reaction was heatedto 60° C. for 1 h, after which the reaction was diluted with water and1N hydrochloric acid solution and extracted with dichloromethane. Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. The crude material was purified via silica gelchromatography utilizing a 3-8% methanol in dichloromethane gradient todeliver the desired compound, Compound I-472 (39.6 mg, 37% yield) as awhite solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.55 (d, 1H), 8.26 (br. s, 1H), 7.36 (s, 1H),7.26-7.30 (m, 1H), 7.07-7.16 (m, 3H), 6.84-6.91 (m, 1H), 6.62-6.67 (m,1H), 5.95 (s, 2H), 4.60 (s, 2H), 3.17 (s, 3H); 1 N—H proton notobserved.

Compound I-486

The title compound was prepared following general procedure C, except4-sulfamoylbutanoic acid was the acid reactant, and 2.5 equivalents ofT3P was used. The crude material was purified via silica gelchromatography utilizing a 3-10% methanol in dichloromethane gradient todeliver the desired compound, Compound I-486 (14.7 mg, 15% yield) as awhite solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.78 (s, 1H), 8.66 (d, 1H), 8.12 (d, 1H), 7.52(s, 1H), 7.25-7.32 (m, 1H), 7.07-7.13 (m, 1H), 7.02-7.07 (m, 1H),6.86-6.91 (m, 2H, 2 shifts isochronous), 5.97 (s, 2H), 3.19 (t, 2H),2.71 (t, 2H), 2.21 (m, 2H).

Compound I-496

To 0° C. suspension of Intermediate 2 (1 equiv.) in dichloromethane wasadded trimethylaluminum (2M solution in toluene, 0.45 equiv.). Thereaction was warmed to 23° C. after which α,α-dimethyl-γ-butyrolactone(1.1 equiv.) was added. The reaction was heated to 80° C. for 16 h,cooled to 23° C., then diluted with saturated ammonium chloridesolution, extracted with ethyl acetate, and washed with 1N hydrochloricacid solution. The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. The crude material waspurified via reverse phase HPLC utilizing 5-75% of an acetonitrile inwater gradient to deliver the desired compound, Compound I-496 (7.7 mg,25% yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.71 (d, 1H), 8.47 (d, 1H), 8.34 (d, 1H), 7.41(s, 1H), 7.17-7.24 (m, 1H), 7.01-7.07 (m, 1H), 6.95-6.99 (m, 1H),6.85-6.90 (m, 1H), 6.60 (d, 1H), 6.00 (s, 2H), 4.15 (t, 2H), 2.04 (t,2H), 1.29 (s, 6H).

Compound I-501

To a mixture of Intermediate 1 (1 equiv.) and5-(trifluoromethyl)pyrrolidin-2-one (1.2 equiv.) in 1,4-dioxane wasadded cesium carbonate (1.5 equiv.). The reaction was heated to 100° C.for 16 h, after which the reaction was diluted with water, extractedwith dichloromethane, and washed with saturated sodium bicarbonatesolution. The combined organic layers were dried over sodium sulfate,filtered, and concentrated in vacuo. The crude material was purified viareverse phase HPLC utilizing a 10-95% acetonitrile in water gradient todeliver the desired compound, Compound I-501 (13.4 mg, 13% yield) as anoff-white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.76 (d, 1H), 8.49 (d, 1H), 7.38 (s, 1H),7.21-7.26 (m, 1H), 7.03-7.07 (m, 1H), 6.98-7.02 (m, 1H), 6.86-6.92 (m,1H), 6.61 (d, 1H), 6.01 (s, 2H), 5.34-5.39 (m, 1H), 2.88-2.99 (m, 1H),2.58-2.70 (m, 2H), 2.40-2.46 (m, 1H).

Compound I-503

To a mixture of Intermediate 1 (1 equiv.) and isothiazolidine1,1-dioxide (1.2 equiv.) in 1,4-dioxane was added cesium carbonate (1.5equiv.). The reaction was heated to 100° C. for 16 h, after which thereaction was diluted with water, and extracted with ethyl acetate. Thecombined organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. The crude material was purified via silica gelchromatography utilizing a 3-10% methanol in dichloromethane gradient todeliver the desired compound, Compound I-503 (71.3 mg, 73% yield) as anoff-white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.57 (d, 1H), 8.47 (d, 1H), 7.36 (s, 1H),7.20-7.25 (m, 1H), 7.03-7.07 (m, 1H), 6.96-7.01 (m, 1H), 6.84-6.88 (m,1H), 6.61 (m, 1H), 5.99 (s, 2H), 4.27 (t, 2H), 3.44 (t, 2H), 2.66 (t,2H).

Compound I-506

To a mixture of Intermediate 1 (1 equiv.) and piperidin-2-one (1.2equiv.) in 1,4-dioxane was added cesium carbonate (1.5 equiv.). Thereaction was heated to 100° C. for 16 h, after which the reaction wasdiluted with water, extracted with dichloromethane, and washed with 1Nsodium hydroxide solution. The combined organic layers were dried oversodium sulfate, filtered, and concentrated in vacuo. The crude materialwas purified via reverse phase HPLC utilizing 5-95% of an acetonitrilein water gradient to deliver the desired compound, Compound I-506 (4.9mg, 5% yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.64 (d, 1H), 8.48 (d, 1H), 7.38 (s, 1H),7.19-7.23 (m, 1H), 7.03-7.07 (m, 1H), 6.97-7.01 (m, 1H), 6.85-6.88 (m,1H), 6.60 (d, 1H), 6.00 (s, 2H), 4.00 (t, 2H), 2.65 (t, 2H), 1.98-2.07(m, 4H).

Compound I-512

To a mixture of Intermediate 1 (1 equiv.) and5,5-dimethylpyrrolidin-2-one (1.2 equiv.) in 1,4-dioxane was addedcesium carbonate (1.5 equiv.). The reaction was heated to 100° C. for 16h, after which the reaction was diluted with water, extracted withdichloromethane, and washed with saturated sodium bicarbonate solution.The combined organic layers were dried over sodium sulfate, filtered,and concentrated in vacuo. The crude material was purified via reversephase HPLC utilizing a 10-95% acetonitrile in water gradient to deliverthe desired compound, Compound I-512 (0.6 mg, 1% yield) as an off-whitesolid.

¹H-NMR (500 MHz, CDCl₃) δ 8.69 (d, 1H), 8.49 (d, 1H), 7.28 (s, 1H),7.20-7.25 (m, 1H), 7.01-7.06 (m, 1H), 6.98-7.01 (m, 1H), 6.89-6.95 (m,1H), 6.60 (d, 1H), 5.97 (s, 2H), 2.67 (t, 2H), 2.14 (t, 2H), 1.63 (s,6H).

Compounds I-526 and Compound I-527

To a mixture of Intermediate 1 (1 equiv.) and an inseparable mixture of3-methyl-3-(methylsulfonyl)pyrrolidin-2-one and4-hydroxy-2-methyl-2-(methylsulfonyl)-butanamide (combined, 1 equiv.) in1,4-dioxane was added cesium carbonate (1.5 equiv.). The reaction washeated to 100° C. for 16 h, after which the reaction was diluted withwater, and extracted with ethyl acetate. The combined organic layerswere dried over sodium sulfate, filtered, and concentrated in vacuo. Thecrude material was purified via reverse phase HPLC utilizing a 5-95%acetonitrile in water gradient to deliver the desired compounds,Compound I-526 (0.5 mg, 2% yield), and Compound I-527 (1.3 mg, 5% yield)as white solids.

¹H-NMR for Compound I-526 (500 MHz, CDCl₃) δ 8.73 (d, 1H), 8.49 (d, 1H),7.37 (s, 1H), 7.20-7.25 (m, 1H), 7.02-7.06 (m, 1H), 6.96-7.01 (m, 1H),6.84-6.89 (m, 1H), 6.61 (d, 1H), 6.01 (s, 2H), 4.28-4.33 (m, 1H),4.18-4.23 (m, 1H), 3.20-3.25 (m, 1H), 3.12 (s, 3H), 2.29-2.35 (m, 1H),2.87 (s, 3H).

¹H-NMR for Compound I-527 (500 MHz, CDCl₃) δ 8.50 (d, 1H), 8.44 (d, 1H),7.38 (s, 1H), 7.20-7.26 (m, 1H), 7.06-7.11 (m, 1H), 7.02-7.06 (m, 1H),6.95-7.03 (m, 1H), 6.65 (d, 1H), 6.00 (d, 1H), 5.98 (d, 1H), 5.91 (br.s, 1H), 4.82-4.86 (m, 1H), 4.74-4.78 (m, 1H), 3.03 (s, 3H), 2.86-2.90(m, 1H), 2.48-2.52 (m, 1H), 1.76 (s, 3H).

Compound I-533

To a mixture of Intermediate 1 (1 equiv.) and pyrrolidine-2,5-dione (1.3equiv.) in 1,4-dioxane was added cesium carbonate (1.5 equiv.). Thereaction was heated to 100° C. for 16 h, after which the reaction wasdiluted with water, extracted with ethyl acetate, and washed with 1Nsodium hydroxide solution. The combined organic layers were dried oversodium sulfate, filtered, and concentrated in vacuo. The crude materialwas purified via reverse phase HPLC utilizing a 5-95% acetonitrile inwater gradient to deliver the desired compound, Compound I-533 (3.8 mg,5% yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.86 (d, 1H), 8.47 (d, 1H), 7.42 (s, 1H),7.20-7.24 (m, 1H), 7.01-7.06 (m, 1H), 6.96-7.00 (m, 1H), 6.81-6.85 (m,1H), 6.59 (d, 1H), 6.02 (s, 2H), 3.02 (s, 4H).

Compound I-534

To a mixture of Intermediate 1 (1 equiv.) and5-oxopyrrolidine-2-carboxamide (1.2 equiv.) in 1,4-dioxane was addedcesium carbonate (1.5 equiv.). The reaction was heated to 100° C. for 24h, after which the reaction was diluted with water and extracted withethyl acetate. The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. The crude material waspurified via reverse phase HPLC utilizing a 5-75% acetonitrile in watergradient to deliver the desired compound, Compound I-534 (0.6 mg, 1%yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.62 (d, 1H), 8.50 (d, 1H), 7.31 (s, 1H),6.99-7.07 (m, 3H), 6.61 (d, 1H), 6.01 (d, 1H), 5.85 (d, 2H), 5.29 (s,2H), 4.92-4.96 (m, 1H), 2.87-2.93 (m, 1H), 2.58-2.63 (m, 1H), 2.43-2.55(m, 2H).

Compound I-590

To a mixture of Intermediate 1 (1 equiv.) and5-oxopyrrolidine-3-carboxamide (1.3 equiv.) in 1,4-dioxane was addedcesium carbonate (1.5 equiv.). The reaction was heated to 100° C. for 16h, after which the reaction was diluted with water, extracted with ethylacetate, and washed with 1N hydrochloric acid solution. The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. The crude material was purified via silica gelchromatography utilizing a 5-12% methanol in dichloromethane gradient todeliver the desired compound, Compound I-590 (3.2 mg, 3% yield) as a tansolid.

¹H-NMR (500 MHz, CD₃OD) δ 8.76 (d, 1H), 8.74 (d, 1H), 7.53 (s, 1H),7.25-7.29 (m, 1H), 7.07-7.11 (m, 1H), 7.02-7.07 (m, 1H), 6.91 (d, 1H),6.83-6.87 (m, 1H), 5.97 (s, 2H), 4.26-4.37 (m, 2H), 3.45-3.49 (m, 1H),2.84-2.94 (m, 2H).

Compound I-691

To a mixture of Intermediate 1 (1 equiv.) and ethyl3-methyl-2-oxopyrrolidine-3-carboxylate (1.2 equiv.) in 1,4-dioxane wasadded cesium carbonate (1.5 equiv.). The reaction was heated to 75° C.for 16 h, after which the reaction was diluted with saturated ammoniumchloride solution, and extracted with dichloromethane. The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. The crude material was purified via silica gelchromatography utilizing a 3-7% methanol in dichloromethane gradient todeliver the desired compound, Compound I-691 (377 mg, 92% yield) as awhite solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.68 (d, 1H), 8.48 (d, 1H), 7.37 (s, 1H),7.19-7.25 (m, 1H), 7.01-7.06 (m, 1H), 6.96-7.01 (m, 1H), 6.86-6.90 (m,1H), 6.60 (d, 1H), 6.00 (s, 2H), 4.26 (q, 2H), 4.15-4.21 (m, 2H),2.75-2.80 (m, 1H), 2.17-2.23 (m, 1H), 1.59 (s, 3H), 1.30 (t, 3H).

Compound I-604

To a suspension of Compound I-591 (1 equiv.) in 1:1tetrahydrofuran/water was added a 1M aqueous solution of sodiumhydroxide (2 equiv.). The reaction was stirred at room temperature for 2h, after which the reaction was concentrated to ˜50% of its volume,acidified by the addition of 1M aqueous hydrochloric acid solution, andextracted with ethyl acetate. The combined organic layers were driedover sodium sulfate, filtered, and concentrated in vacuo to deliver thedesired compound, Compound I-604 (154.6 mg, 95% yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.77-8.80 (m, 2H, 2 overlapping shifts), 7.57(s, 1H), 7.28-7.32 (m, 1H), 7.09-7.13 (m, 1H), 7.04-7.09 (m, 1H), 6.94(d, 1H), 6.86-6.90 (m, 1H), 6.00 (s, 2H), 4.26-4.31 (m, 1H), 4.16-4.20(m, 1H), 2.75-2.79 (m, 1H), 2.27-2.31 (m, 1H), 1.54 (s, 3H).

Compound I-605

To a −78° C. solution of Compound I-604 (1 equiv.) in dichloromethanewas added oxalyl chloride (2M solution in dichloromethane, 2.5 equiv.).The reaction was stirred at −78° C. for 30 min, then warmed up to 0° C.,and stirred at that temperature for 1 h. The reaction was thenconcentrated in vacuo, reconstituted in dichloromethane, and cooled to−78° C. To this solution was added cyclopropylamine (5 equiv.), afterwhich the reaction was allowed to warm up to room temperature. After 20min, the reaction was concentrated in vacuo. The crude material waspurified via silica gel chromatography utilizing a 1-8% methanol indichloromethane gradient to deliver the desired compound, Compound I-604(14.5 mg, 23% yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.70 (d, 1H), 8.49 (d, 1H), 7.36 (s, 1H),7.20-7.25 (m, 1H), 7.01-7.08 (m, 1H), 6.97-7.01 (m, 1H), 6.86-6.90 (m,1H), 6.60 (d, 1H), 6.00 (s, 2H), 4.06-4.09 (m, 2H), 3.00-3.06 (m, 1H),2.75-2.80 (m, 1H), 2.14-2.29 (m, 1H), 1.58 (s, 3H), 0.78-0.82 (m, 2H),0.51-0.54 (m, 2H); 1 N—H proton not observed.

Compound I-606

To a −78° C. solution of Compound I-604 (1 equiv.) in dichloromethanewas added a 2M in dichloromethane solution of oxalyl chloride (2.5equiv.). The reaction was stirred at −78° C. for 30 minutes, then warmedup to 0° C., and stirred at that temperature for 1 h. The reaction wasthen concentrated in vacuo, reconstituted in dichloromethane, and cooledto −78° C. To this solution was added ammonium hydroxide solution (50equiv.), after which the reaction was allowed to warm up to roomtemperature. After 20 minutes, the reaction was diluted in water andextracted with ethyl acetate. The combined organic layers were driedover sodium sulfate, filtered, and concentrated in vacuo to deliver thedesired compound, Compound I-619 (43.3 mg, 75% yield) as an off-whitesolid.

¹H-NMR (500 MHz, CDCl₃) δ 8.71 (d, 1H), 8.49 (d, 1H), 7.37 (s, 1H),7.20-7.25 (m, 1H), 7.03-7.07 (m, 1H), 6.97-7.01 (m, 1H), 6.86-6.91 (m,1H), 6.60 (d, 1H), 6.00 (s, 2H), 4.07-4.13 (m, 2H), 2.97-3.03 (m, 1H),2.17-2.22 (m, 1H), 1.65 (s, 3H); 2 N—H protons not observed.

Compound I-612

A suspension of Intermediate 1 (1 equiv) and potassium((2-carboxylatoethyl)sulfonyl)amide (1.15 equiv.) in DMSO was stirred atroom temperature for 72 h. The reaction was diluted in water, washedwith dichloromethane, acidified by the addition of 1M hydrochloric acidsolution, and extracted with ethyl acetate. The combined organic layerswere dried over sodium sulfate, filtered, and concentrated in vacuo todeliver the acid intermediate. To a suspension of this acid intermediatein dichloromethane was added triethylamine (3 equiv.), followed byoxalyl chloride (2M solution in dichloromethane, 2 equiv). After 15 min,the reaction was concentrated in vacuo. The crude material was purifiedvia reverse phase HPLC utilizing a 5-75% acetonitrile in water gradientto deliver the desired compound, Compound I-612 (5.8 mg, 12% yield) as awhite solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.86 (d, 1H), 8.47 (d, 1H), 7.43 (s, 1H),7.19-7.24 (m, 1H), 7.01-7.06 (m, 1H), 6.96-7.01 (m, 1H), 6.83-6.88 (m,1H), 6.63 (d, 1H), 6.02 (s, 2H), 3.89 (t, 2H), 3.35 (t, 2H).

Compound I-615

To a mixture of Intermediate 1 (1 equiv.) and 3-hydroxypyrrolidin-2-one(1.2 equiv.) in 1,4-dioxane was added cesium carbonate (1.5 equiv.). Thereaction was heated to 70° C. for 12 h, after which the reaction wasdiluted with water and extracted with ethyl acetate. The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo to deliver the desired compound, Compound I-615(59.7 mg, 48% yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ 8.48 (d, 1H), 8.46 (d, 1H), 7.32 (s, 1H),7.19-7.24 (m, 1H), 7.02-7.07 (m, 1H), 6.98-7.02 (m, 1H), 6.89-6.94 (m,1H), 6.60 (d, 1H), 5.97 (s, 2H), 5.92-5.96 (m, 1H), 3.60-3.65 (m, 1H),3.47-3.52 (m, 1H), 2.82-2.86 (m, 1H), 2.33-2.41 (m, 1H); 1 O—H protonnot observed.

Compound I-628

A solution of1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamidehydrochloride (generated in step 3 of general procedure A, by using1-(isoxazol-3-yl)ethanone in step 1 and 2-fluorobenzylhydrazine in step2, 1 equiv.), methyl 4-oxotetrahydrothiophene-3-carboxylate (3 equiv.),and 1,8-diazabicyclo[5.4.0]undec-7-ene (1 equiv.) in pyridine was heatedto 80° C. for 12 h. The reaction was concentrated in vacuo, slurried inmethanol, concentrated in vacuo, and slurried again in methanol. Theprecipitate was filtered and dried to provide the desired cyclic sulfideintermediate (190 mg, 45% yield) as a light-tan solid. To a solution ofthis sulfide intermediate (1 equiv.) in dichloromethane was addedperacetic acid (2.3 equiv.). After 30 min, the reaction was concentratedin vacuo, slurried in water, and filtered to deliver the desiredcompound, Compound I-628 (148.8 mg, 73% yield) as an off-white solid.

¹H-NMR (500 MHz, CDCl₃) δ 10.2 (br. s, 1H), 8.56 (s, 1H), 7.31-7.34 (m,1H), 7.30 (s, 1H), 7.07-7.12 (m, 3H), 6.64 (m, 1H), 5.93 (s, 2H), 4.36(s, 2H), 4.35 (s, 2H).

Compound I-632

A suspension of Compound I-628 (1 equiv.) in phosphorus oxychloride (62equiv.) was heated to 90° C. for 2 h, after which the reaction mixturewas concentrated in vacuo to afford the desired chloropyrimidineintermediate (155 mg, 100% yield) as a tan solid. To a suspension ofthis intermediate (1 equiv.) in dioxane was added an ammonium hydroxidesolution (440 equiv.). The reaction was stirred at 23° C. for 15 h, thenheated to 60° C. for 1 h, after which the mixture was diluted in waterand extracted with ethyl acetate. The combined organic layers were driedover sodium sulfate, filtered, and concentrated in vacuo to deliver thedesired compound, Compound I-632 (44.5 mg, 60% yield) as a tan solid.

¹H-NMR (500 MHz, DMSO-d₆) δ 9.09 (d, 1H), 7.51 (s, 1H), 7.31-7.35 (m,1H), 7.27 (d, 1H), 7.21-7.24 (m, 1H), 7.09-7.13 (m, 1H), 6.83-6.87 (m,1H), 5.90 (s, 2H), 4.49 (s, 2H), 4.31 (s, 2H).

Compound I-497 and I-524

A solution of Intermediate 2 (1 equiv.), triethylamine (3.5 equiv.),DMAP (0.1 equiv.), and 2-chloro-2-oxoethylacetate (2.2 equiv.) indichloromethane was heated to 60° C. for 26 h. Solvent removed in vacuo,and crude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-497 (30 mg, 23% yield) as a white solid,and a side product, Compound I-524 (4.5 mg, 4% yield) as a white solid.

¹H-NMR for Compound I-497 (500 MHz, DMSO-d₆) δ ppm 11.37 (m, 1H), 9.11(d, 1H), 8.75 (d, 1H), 7.94 (m, 1H), 7.66 (s, 1H), 7.35 (m, 1H), 7.27(d, 2H), 7.11 (m, 1H), 6.89 (m, 1H), 5.93 (s, 2H), 4.77 (s, 2H), 2.12(s, 3H).

¹H-NMR for Compound I-524 (500 MHz, DMSO-d₆) δ ppm 11.13 (m, 1H), 9.09(m, 1H), 8.72 (m, 1H), 8.00 (m, 1H), 7.65 (s, 1H), 7.35 (m, 1H), 7.26(s, 2H), 7.12 (m, 1H), 6.88 (m, 1H), 5.93 (s, 2H), 2.15 (s, 3H).

Compound I-499

Into a slurry of Compound I-497 (1 equiv.) in methanol was added asolution of potassium carbonate (0.5 equiv.) in water. After stirringfor 1 h at 23 C, an additional 0.5 equivalents of potassium carbonate inwater was added to the vessel, along with THF (equal volume to startingvolume of methanol). Reaction was allowed to stir for an additional 1 hat 23° C. Solvent was removed in vacuo, and the resulting crude materialwas purified via silica gel chromatography utilizing a 0-5% methanol indichloromethane gradient to deliver the desired compound, Compound I-499(10.5 mg, 17% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 10.43 (m, 1H), 9.11 (m, 1H), 8.75 (m,1H), 8.01 (m, 1H), 7.68 (s, 1H), 7.34 (m, 1H), 7.24 (m, 2H), 7.12 (m,1H), 6.89 (m, 1H), 5.93 (s, 2H), 5.61 (m, 1H), 4.11 (m, 2H).

Compound I-525

The title compound was prepared following general procedure C in libraryformat, except 4-(benzyloxy)tetrahydro-2H-pyran-4-carboxylic acid wasthe acid reactant, and the crude material was purified via reverse phaseHPLC to deliver the desired compound, Compound I-525 (9 mg, 27% yield)as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.39 (m, 1H), 8.91 (m, 1H), 8.56 (s,1H), 8.36 (m, 1H), 7.53 (m, 1H), 7.38 (m, 5H), 7.26 (m, 1H), 7.07 (s,3H), 6.65 (s, 1H), 6.02 (s, 2H), 4.51 (s, 2H), 3.96 (m, 2H), 3.87 (m,2H), 2.28 (m, 2H), 1.99 (m, 2H).

Compound I-528

The title compound was prepared following general procedure C in libraryformat, except 2-methoxyacetic acid was the acid reactant, and the crudematerial was purified via reverse phase HPLC to deliver the desiredcompound, Compound I-528 (7 mg, 58% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.18 (m, 1H), 8.75 (m, 1H), 8.47 (m,1H), 8.18 (m, 1H), 7.50 (m, 1H), 7.21 (m, 1H), 7.05 (m, 1H), 6.97 (m,1H), 6.83 (m, 1H), 6.61 (m, 1H), 6.05 (m, 2H), 4.08 (m, 2H), 3.52 (s,3H).

Compound I-532

The title compound was prepared following general procedure C in libraryformat, except oxazole-4-carboxylic acid was the acid reactant, and thecrude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-532 (3.8 mg, 15% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 10.39 (m, 1H), 9.09 (m, 2H), 8.82 (m,1H), 8.65 (m, 1H), 8.11 (m, 1H), 7.73 (m, 1H), 7.29 (m, 3H), 7.13 (m,1H), 6.88 (m, 1H), 5.94 (m, 2H).

Compound I-547

The title compound was prepared following general procedure C in libraryformat, except 3-methoxypropanoic acid was the acid reactant, and thecrude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-547 (4.9 mg, 20% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.09 (m, 1H), 9.09 (m, 1H), 8.72 (m,1H), 8.02 (m, 1H), 7.64 (s, 1H), 7.34 (m, 1H), 7.23 (m, 2H), 7.12 (m,1H), 6.89 (m, 1H), 5.92 (s, 2H), 3.61 (t, 2H), 3.23 (s, 3H), 2.70 (t,2H).

Compound I-548

The title compound was prepared following general procedure C in libraryformat, except tosylalanine was the acid reactant, and the crudematerial was purified via reverse phase HPLC to deliver the desiredcompound, Compound I-548 (3.1 mg, 9% yield) as a white solid.

Compound I-549

The title compound was prepared following general procedure C in libraryformat, except thiazole-4-carboxylic acid was the acid reactant, and thecrude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-549 (3.7 mg, 14% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 10.20 (m, 1H), 9.31 (m, 1H), 9.09 (m,1H), 8.84 (m, 1H), 8.72 (m, 1H), 8.14 (m, 1H), 7.73 (m, 1H), 7.29 (m,3H), 7.13 (m, 1H), 6.89 (m, 1H), 5.94 (m, 2H).

Compound I-550

The title compound was prepared following general procedure C in libraryformat, except 1H-pyrrole-2-carboxylic acid was the acid reactant, andthe crude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-550 (3.4 mg, 13% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.84 (m, 1H), 10.84 (m, 1H), 9.09 (m,1H), 8.73 (m, 1H), 8.16 (m, 1H), 7.68 (s, 1H), 7.36 (m, 2H), 7.24 (m,2H), 7.13 (m, 1H), 7.06 (m, 1H), 6.88 (m, 1H), 6.19 (m, 1H), 5.94 (s,2H).

Compound I-551

The title compound was prepared following general procedure C in libraryformat, except 1-cyanocyclopropane-1-carboxylic acid was the acidreactant, and the crude material was purified via reverse phase HPLC todeliver the desired compound, Compound I-551 (3.3 mg, 13% yield) as awhite solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.02 (m, 1H), 9.09 (m, 1H), 8.74 (m,1H), 7.88 (m, 1H), 7.67 (s, 1H), 7.33 (m, 1H), 7.27 (m, 1H), 7.23 (m,1H), 7.12 (m, 1H), 6.89 (m, 1H), 5.94 (s, 2H), 1.74 (m, 4H).

Compound I-552

The title compound was prepared following general procedure C in libraryformat, except thiazole-5-carboxylic acid was the acid reactant, and thecrude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-552 (2.3 mg, 9% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.71 (m, 1H), 9.35 (m, 1H), 9.12 (m,1H), 8.96 (m, 1H), 8.79 (m, 1H), 8.08 (m, 1H), 7.70 (m, 1H), 7.34 (m,1H), 7.24 (m, 2H), 7.12 (m, 1H), 6.89 (m, 1H), 5.95 (m, 2H).

Compound I-553

The title compound was prepared following general procedure C in libraryformat, except 6-oxo-1,6-dihydropyridine-2-carboxylic acid was the acidreactant, and the crude material was purified via reverse phase HPLC todeliver the desired compound, Compound I-553 (1.9 mg, 7% yield) as awhite solid.

Compound I-554

The title compound was prepared following general procedure C in libraryformat, except 3-methoxyisoxazole-5-carboxylic acid was the acidreactant, and the crude material was purified via reverse phase HPLC todeliver the desired compound, Compound I-554 (4.6 mg, 17% yield) as awhite solid.

Compound I-555

The title compound was prepared following general procedure C in libraryformat, except pyrimidine-4-carboxylic acid was the acid reactant, andthe crude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-555 (1.6 mg, 6% yield) as a white solid.

Compound I-556

The title compound was prepared following general procedure C in libraryformat, except oxazole-5-carboxylic acid was the acid reactant, and thecrude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-556 (4.4 mg, 17% yield) as a white solid.

Compound I-557

The title compound was prepared following general procedure C in libraryformat, except oxazole-4-carboxylic acid was the acid reactant, and thecrude material was purified by reverse phase HPLC to deliver the desiredcompound, Compound I-557 (4.4 mg, 17% yield) as a white solid.

Compound I-558

The title compound was prepared following general procedure C in libraryformat, except cyclopropanecarboxylic acid was the acid reactant, andthe crude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-558 (5.1 mg, 21% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.42 (m, 1H), 9.11 (m, 1H), 8.69 (m,1H), 8.01 (m, 1H), 7.66 (m, 1H), 7.34 (m, 1H), 7.24 (m, 2H), 7.12 (m,1H), 6.89 (m, 1H), 5.93 (m, 2H), 2.12 (m, 1H), 0.87 (d, 4H).

Compound I-559

The title compound was prepared following general procedure C in libraryformat, except (S)-2-methoxy-2-phenylacetic acid was the acid reactant,and the crude material was purified via reverse phase HPLC to deliverthe desired compound, Compound I-559 (6.8 mg, 24% yield) as a whitesolid.

¹H-NMR (500 MHz, DMSO-d₆) δ 11.03 (m, 1H), 9.09 (m, 1H), 8.72 (m, 1H),7.96 (m, 1H), 7.67 (m, 1H), 7.51 (m, 2H), 7.36 (m, 4H), 7.23 (m, 2H),7.12 (m, 1H), 6.87 (m, 1H), 5.93 (m, 2H), 5.12 (m, 1H), 3.34 (s, 3H).

Compound I-560

The title compound was prepared following general procedure C in libraryformat, except furan-2-carboxylic acid was the acid reactant, and thecrude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-560 (5.2 mg, 20% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.10 (m, 1H), 9.09 (m, 1H), 8.75 (m,1H), 8.10 (m, 1H), 8.00 (m, 1H), 7.78 (m, 1H), 7.69 (m, 1H), 7.34 (m,1H), 7.24 (m, 2H), 7.12 (m, 1H), 6.89 (m, 1H), 6.73 (m, 1H), 5.94 (s,2H).

Compound I-561

The title compound was prepared following general procedure C in libraryformat, except thiophene-2-carboxylic acid was the acid reactant, andthe crude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-561 (3.9 mg, 15% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.39 (m, 1H), 9.10 (m, 1H), 8.78 (m,1H), 8.36 (m, 1H), 8.10 (m, 1H), 7.95 (m, 1H), 7.70 (s, 1H), 7.34 (m,1H), 7.25 (m, 3H), 7.12 (m, 1H), 6.88 (m, 1H), 5.95 (m, 2H).

Compound I-562

The title compound was prepared following general procedure C in libraryformat, except 2-ethoxyacetic acid was the acid reactant, and the crudematerial was purified via reverse phase HPLC to deliver the desiredcompound, Compound I-562 (5.7 mg, 23% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 10.70 (m, 1H), 9.10 (m, 1H), 8.73 (m,1H), 8.00 (m, 1H), 7.66 (m, 1H), 7.33 (m, 1H), 7.23 (m, 2H), 7.11 (m,1H), 6.89 (m, 1H), 5.93 (s, 2H), 4.17 (s, 2H), 3.55 (m, 2H), 1.17 (m,3H).

Compound I-563

The title compound was prepared following general procedure C in libraryformat, except 2-(methylsulfonyl)acetic acid was the acid reactant, andthe crude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-563 (3 mg, 11% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.53 (m, 1H), 9.08 (m, 1H), 8.78 (m,1H), 7.99 (m, 1H), 7.66 (m, 1H), 7.34 (m, 1H), 7.23 (m, 2H), 7.12 (m,1H), 6.91 (m, 1H), 5.93 (m, 2H), 4.46 (m, 2H), 3.17 (s, 3H).

Compound I-564

The title compound was prepared following general procedure C in libraryformat, except 3-cyclopropyl-1H-pyrazole-5-carboxylic acid was the acidreactant, and the crude material was purified via reverse phase HPLC todeliver the desired compound, Compound I-564 (1.2 mg, 4% yield) as awhite solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.84 (br s, 1H), 9.10 (m, 1H), 8.77 (m,1H), 8.07 (m, 1H), 7.72 (m, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 7.23 (m,1H), 7.12 (m, 1H), 6.89 (m, 1H), 6.61 (m, 1H), 5.95 (m, 2H), 1.96 (m,1H), 0.98 (m, 2H), 0.76 (m, 2H).

Compound I-565

The title compound was prepared following general procedure C in libraryformat, except 2-acetoxy-2-phenylacetic acid was the acid reactant, andthe crude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-565 (4.1 mg, 14% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.60 (m, 1H), 9.08 (m, 1H), 8.72 (m,1H), 7.92 (m, 1H), 7.65 (m, 1H), 7.59 (m, 2H), 7.41 (m, 3H), 7.33 (m,1H), 7.23 (m, 2H), 7.11 (m, 1H), 6.88 (m, 1H), 6.17 (s, 1H), 5.92 (s,2H), 2.15 (s, 3H).

Compound I-569

The title compound was prepared following general procedure C in libraryformat, except 1-methylcyclopropane-1-carboxylic acid was the acidreactant, and the crude material was purified via reverse phase HPLC todeliver the desired compound, Compound I-569 as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.81 (m, 1H), 8.69 (m, 1H), 8.18 (m, 1H),7.59 (m, 1H), 7.31 (m, 1H), 7.10 (m, 2H), 6.93 (m, 2H), 6.01 (m, 2H),1.52 (s, 3H), 1.32 (m, 2H), 0.84 (m, 2H).

Compound I-570

The title compound was prepared following general procedure C in libraryformat, except tetrahydrofuran-2-carboxylic acid was the acid reactant,and the crude material was purified via reverse phase HPLC to deliverthe desired compound, Compound I-570 as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.79 (m, 1H), 8.72 (m, 1H), 8.17 (m, 1H),7.55 (m, 1H), 7.29 (m, 1H), 7.09 (m, 2H), 6.92 (m, 2H), 5.99 (m, 2H),4.53 (m, 1H), 4.13 (m, 1H), 3.98 (m, 1H), 2.39 (m, 1H), 2.14 (m, 1H),2.01 (m, 2H).

Compound I-571

The title compound was prepared following general procedure C in libraryformat, except 2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid was the acid reactant, and the crude material waspurified via reverse phase HPLC to deliver the desired compound,Compound I-571 as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.79 (d, 1H), 8.69 (d, 1H), 8.09 (d, 1H),7.54 (s, 1H), 7.43 (d, 1H), 7.32-7.25 (m, 1H), 7.14-7.01 (m, 2H),6.96-6.89 (m, 1H), 6.88 (d, 1H), 5.98 (s, 2H), 4.70 (s, 2H), 1.91 (d,3H).

Compound I-572

The title compound was prepared following general procedure C in libraryformat, except 3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid was theacid reactant, and the crude material was purified via reverse phaseHPLC to deliver the desired compound, Compound I-572 as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ 8.79 (m, 2H), 8.19 (m, 1H), 7.64 (m, 2H), 7.57(m, 1H), 7.48 (m, 3H), 7.30 (m, 1H), 7.08 (m, 2H), 6.92 (m, 2H), 5.99(m, 2H), 3.63 (d, 3H).

Compound I-574

The title compound was prepared following general procedure C in libraryformat, except tetrahydro-2H-pyran-4-carboxylic acid was the acidreactant, and the crude material was purified via reverse phase HPLC todeliver the desired compound, Compound I-574 as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.81 (d, 1H), 8.66 (s, 1H), 8.20 (d, 1H),7.54 (s, 1H), 7.30 (m, 1H), 7.09 (m, 2H), 6.93 (m, 1H), 6.88 (d, 1H),5.98 (s, 2H), 4.02 (m, 2H), 3.52 (m, 2H), 2.80 (m, 1H), 1.85 (d, 4H).

Compound I-577

The acetyl-protected intermediate was prepared following generalprocedure C in library format, except 2-acetoxybenzoic acid was the acidreactant. The crude material was purified via reverse phase HPLC todeliver the desired intermediate. The intermediate was then dissolved ina methanol:water mixture (8:1) and treated with lithium hydroxide (4.5equiv.) and a small amount of THF (300 μL). After reaction was complete,volatiles were removed in vacuo, and the residue was treated with 1N HClsolution until pH was ˜4. The mixture was extracted with ethyl acetate,and the organic layers were washed with water and brine. Contents weredried over sodium sulfate, filtered, and concentrated to deliver thedesired compound, Compound I-577 (10 mg, 33% yield over 2 steps) as awhite solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.81 (m, 1H), 11.12 (m, 1H), 9.10 (d,1H), 8.79 (m, 1H), 8.20 (m, 1H), 8.00 (m, 1H), 7.66 (s, 1H), 7.51 (m,1H), 7.34 (m, 1H), 7.28 (d, 1H), 7.23 (m, 1H), 7.08 (m, 3H), 6.90 (m,1H), 5.96 (s, 2H).

Compound I-579

A solution of 2-cyanoacetic acid (4 equiv.) in DMF was cooled to 0° C.,and treated with oxalyl chloride (4.1 equiv.) as a solution in DMF. Gasevolution was observed, and contents were stirred at 0° C. for 30 min.Intermediate 2 (1 equiv.) was added to the reaction, and contentsstirred for 18 h as it was allowed to warmed to 23° C. Solvents wereremoved in vacuo, and the crude material was purified via reverse phaseHPLC to deliver the desired compound, Compound I-579 (2.3 mg, 10% yield)as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.47 (m, 1H), 9.10 (d, 1H), 8.78 (m,1H), 7.94 (m, 1H), 7.65 (s, 1H), 7.34 (d, 1H), 7.24 (m, 2H), 7.12 (m,1H), 6.91 (t, 1H), 5.92 (s, 2H), 4.05 (s, 2H).

Compound I-594

The title compound was prepared following general procedure C in libraryformat, except 2-methyl-2,3-dihydrobenzo[b]thiophene-2-carboxylic acid1,1-dioxide was the acid reactant, and the crude material was purifiedvia reverse phase HPLC to deliver the desired compound, Compound I-594(7.4 mg, 23% yield) as a yellow solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 10.96 (m, 1H), 9.09 (m, 1H), 8.77 (m,1H), 7.93 (m, 1H), 7.79 (m, 1H), 7.68 (s, 2H), 7.57 (m, 2H), 7.34 (m,1H), 7.24 (m, 2H), 7.12 (m, 1H), 6.89 (m, 1H), 5.94 (s, 2H), 4.11 (m,1H), 3.30 (m, 1H), 1.89 (s, 3H).

Compound I-596

The title compound was prepared following general procedure C in libraryformat, except 2-(1,3-dioxoisoindolin-2-yl)acetic acid was the acidreactant, and the crude material was purified via reverse phase HPLC todeliver the desired compound, Compound I-596 (17.4 mg, 56% yield) as awhite solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.60 (m, 1H), 9.09 (m, 1H), 8.74 (m,1H), 7.91 (m, 5H), 7.65 (m, 1H), 7.35 (m, 1H), 7.24 (m, 2H), 7.12 (m,1H), 6.92 (m, 1H), 5.93 (m, 2H), 4.58 (s, 2H).

Compound I-597

The title compound was prepared following general procedure C in libraryformat, except (2-phenylacetyl)glycine was the acid reactant, and thecrude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-597 (4.4 mg, 15% yield) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.83 (m, 1H), 8.68 (m, 1H), 8.24 (m, 1H),7.58 (s, 1H), 7.34 (m, 5H), 7.26 (m, 1H), 7.10 (m, 2H), 6.97 (m, 1H),6.90 (m, 1H), 6.01 (s, 2H), 4.17 (s, 2H), 3.66 (s, 2H).

Compound I-598

The title compound was prepared following general procedure C in libraryformat, except ((benzyloxy)carbonyl)glycine was the acid reactant, andthe crude material was purified via reverse phase HPLC to deliver thedesired compound, Compound 1598 (4 mg, 13% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.15 (m, 1H), 9.10 (d, 1H), 8.73 (m,1H), 7.98 (m, 1H), 7.65 (s, 1H), 7.57 (m, 1H), 7.37 (m, 6H), 7.23 (m,2H), 7.12 (m, 1H), 6.90 (m, 1H), 5.92 (m, 2H), 5.05 (s, 2H), 3.93 (m,2H).

Compound I-599

The title compound was prepared following general procedure C in libraryformat, except 2-(1-oxoisoindolin-2-yl)acetic acid was the acidreactant, and the crude material was purified via reverse phase HPLC todeliver the desired compound, Compound I-599 (11.7 mg, 39% yield) as awhite solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.42 (m, 1H), 9.10 (m, 1H), 8.74 (m,1H), 7.95 (m, 1H), 7.72 (m, 1H), 7.66 (m, 1H), 7.63 (m, 2H), 7.52 (m,1H), 7.34 (m, 1H), 7.24 (m, 2H), 7.13 (m, 1H), 6.92 (m, 1H), 5.93 (m,2H), 4.55 (m, 4H).

Compound I-610

The title compound was prepared following general procedure C in libraryformat, except 2-(2-oxooxazolidin-3-yl)acetic acid was the acidreactant, and the crude material was purified via reverse phase HPLC todeliver the desired compound, Compound I-610 (11.4 mg, 42% yield) as awhite solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.33 (m, 1H), 9.10 (m, 1H), 8.75 (m,1H), 7.96 (m, 1H), 7.64 (m, 1H), 7.35 (m, 1H), 7.24 (m, 2H), 7.12 (m,1H), 6.91 (m, 1H), 5.93 (m, 2H), 4.33 (m, 2H), 4.15 (s, 2H), 3.64 (m,2H).

Compound I-601

The title compound was prepared following general procedure C in libraryformat, except 2-(4-oxoquinazolin-3 (4H)-yl)acetic acid was the acidreactant, and the crude material was purified via reverse phase HPLC todeliver the desired compound, Compound I-601 (3.3 mg, 11% yield) as awhite solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.69 (m, 1H), 9.10 (m, 1H), 8.75 (m,1H), 8.37 (s, 1H), 8.15 (m, 1H), 7.90 (m, 2H), 7.73 (m, 1H), 7.67 (s,1H), 7.56 (m, 1H), 7.34 (m, 1H), 7.24 (m, 2H), 7.13 (m, 1H), 6.93 (m,1H), 5.94 (s, 2H), 4.99 (s, 2H).

Compound I-602

The title compound was prepared following general procedure C in libraryformat, except (2-(1,3-dioxoisoindolin-2-yl)acetyl)glycine was the acidreactant, and the crude material was purified via reverse phase HPLC todeliver the desired compound, Compound I-602 (1.2 mg, 4% yield) as awhite solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.20 (m, 1H), 9.09 (m, 1H), 8.74 (m,1H), 8.62 (m, 1H), 7.98 (m, 1H), 7.91 (s, 2H), 7.88 (s, 2H), 7.64 (s,1H), 7.33 (m, 1H), 7.24 (d, 1H), 7.20 (m, 1H), 7.11 (m, 1H), 6.89 (m,1H), 5.92 (m, 2H), 4.29 (s, 2H), 4.05 (m, 2H).

Compound I-603

The title compound was prepared following general procedure C in libraryformat, except (methoxycarbonyl)glycine was the acid reactant, and thecrude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-603 (2.2 mg, 8% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.13 (m, 1H), 9.09 (m, 1H), 8.73 (m,1H), 7.97 (m, 1H), 7.66 (m, 1H), 7.42 (m, 1H), 7.34 (m, 1H), 7.23 (m,2H), 7.12 (m, 1H), 6.90 (m, 1H), 5.92 (m, 2H), 3.90 (m, 2H), 3.56 (s,3H).

Compound I-592

The title compound was prepared following general procedure C, except2-(phenylsulfonyl)acetic acid was the acid reactant, and the crudematerial was purified via reverse phase HPLC to deliver the desiredcompound, Compound I-592 (1.7 mg, 5% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.44 (m, 1H), 9.10 (m, 1H), 8.75 (m,1H), 7.92 (m, 1H), 7.91 (m, 1H), 7.89 (m, 1H), 7.88 (m, 1H), 7.76 (m,1H), 7.65 (m, 2H), 7.34 (m, 1H), 7.26 (m, 1H), 7.22 (m, 1H), 7.12 (m,1H), 6.91 (m, 1H), 5.92 (m, 2H), 4.67 (m, 2H).

Compound I-594

The title compound was prepared following general procedure C, except2-((4-chlorophenyl)sulfonyl)acetic acid was the acid reactant, and thecrude material was purified by reverse phase HPLC to deliver the desiredcompound, Compound I-594 (5.8 mg, 15% yield) as a white solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.48 (s, 1H), 9.10 (d, 1H), 8.76 (d,1H), 7.92 (m, 2H), 7.87 (m, 1H), 7.76 (m, 2H), 7.65 (s, 1H), 7.34 (m,1H), 7.24 (m, 2H), 7.12 (m, 1H), 6.91 (m, 1H), 5.93 (s, 2H), 4.73 (m,2H).

Compound I-498

To a mixture of5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-pyrimidin-4-amine(intermediate described in WO2012/3405 A1; 1 equiv.), triethylamine (6equiv.), and N,N-dimethylpyridin-4-amine (0.01 equiv.) indichloromethane was added 2-chloro-2-oxoethyl acetate (3 equiv.) at 23°C. Contents were heated to 60° C. and stirred for 18 h. Solvent removedin vacuo, and purification of the crude material via reverse phase HPLCdelivered the desired compound, Compound I-498 (1.0 mg, 2% yield) as asolid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 11.21 (m, 1H), 9.09 (m, 1H), 8.84 (m,1H), 7.61 (m, 1H), 7.34 (m, 1H), 7.27 (m, 1H), 7.22 (m, 1H), 7.12 (m,1H), 6.94 (m, 1H), 5.92 (m, 2H), 4.91 (s, 2H), 2.13 (s, 3H).

Compound I-578

The title compound was prepared following general procedure B, excepttetrahydrofuran-3-amine was the amine reactant, 6 equivalents oftriethylamine was used, and contents were heated to 100° C. as asolution in dioxane/water (4:1) for 24 h. The mixture was cooled to 23°C. and solvent removed in vacuo. The solid was purified via reversephase HPLC to deliver the desired compound, Compound I-578 (12 mg, 53%yield) as a solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.11 (m, 1H), 8.58 (m, 1H), 8.31 (m,1H), 7.61 (m, 1H), 7.34 (m, 1H), 7.24 (m, 2H), 7.11 (m, 1H), 6.89 (m,1H), 5.93 (s, 2H), 4.76 (m, 1H), 4.04 (m, 1H), 3.89 (m, 1H), 3.77 (m,1H), 3.64 (m, 1H), 2.27 (m, 1H), 2.04 (s, 1H).

Compound I-613

A solution of Intermediate 1 (1 equiv.) in DMSO was treated withpotassium benzenesulfonamide (2 equiv.). The resulting reaction mixturewas stirred at 100° C. for 8 h. Contents were filtered, and the filtratewas directly purified via reverse phase HPLC to deliver the desiredcompound, Compound I-613 (7 mg, 26% yield) as a solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.82 (m, 1H), 8.37 (m, 1H), 8.26 (m, 2H),7.58 (m, 1H), 7.47 (m, 2H), 7.31 (m, 2H), 7.11 (m, 2H), 6.94 (m, 2H),5.98 (m, 2H).

Compound I-614

A solution of Intermediate 1 (1 equiv.) in DMSO was treated withpotassium 3,4-dimethoxybenzenesulfonamide (2 equiv.). The resultingreaction mixture was stirred at 100° C. for 8 h. Contents were filtered,and the filtrate was directly purified via reverse phase HPLC to deliverthe desired compound, Compound I-614 (1.3 mg, 5% yield) as a solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.12 (m, 1H), 8.56 (m, 1H), 7.90 (m,1H), 7.60 (m, 1H), 7.38 (m, 2H), 7.27 (d, 2H), 7.12 (m, 1H), 6.92 (m,2H), 5.94 (s, 2H), 3.71 (d, 6H).

Compound I-607

A solution of Intermediate 1 (1 equiv.) in DMSO was treated withpotassium (4-fluorophenyl)methanesulfonamide (2 equiv.). The resultingreaction mixture was stirred at 60° C. for 0.5 h, after which thereaction was diluted with water and 1N hydrochloric acid solution, andextracted with ethyl acetate. The combined organic layers were driedover sodium sulfate, filtered, and concentrated in vacuo. The crudematerial was purified via silica gel chromatography utilizing a 0-5%methanol in dichloromethane gradient to deliver the desired compound,Compound I-607 (2.8 mg, 6% yield) as a solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.79 (m, 1H), 8.45 (m, 1H), 7.52 (m, 1H),7.40 (m, 2H), 7.26 (m, 1H), 6.94 (d, 6H), 5.98 (s, 2H), 5.04 (m, 2H).

Compound I-624

To a solution of 4-fluorobenzenesulfonamide (4 equiv.) in DMF was addedpotassium bis(trimethylsilyl)amide (4 equiv.) at 23° C. After 15 minutesof stirring, Intermediate 1 (1 equiv.) was added and reaction stirredfor 3 days at 75° C. Without workup, product was purified by reversephase HPLC to deliver the desired compound, Compound I-624 (1.9 mg, 7%yield) as a solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.13 (m, 1H), 8.51 (m, 1H), 8.30 (m,2H), 7.40 (m, 2H), 7.27 (m, 2H), 7.15 (m, 3H), 6.95 (m, 1H), 5.99 (s,2H).

Compound I-625

A solution of Intermediate 1 (1 equiv.) in DMSO was treated withpotassium pyridine-3-sulfonamide (1 equiv.) and potassium carbonate (0.5equiv.). The resulting reaction mixture was heated at 150° C. for 10min. in a microwave. Contents were filtered, and the filtrate wasdirectly purified via reverse phase HPLC to deliver the desiredcompound, Compound I-625 (4.4 mg, 33% yield) as a solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.24 (m, 1H), 9.14 (m, 1H), 8.69 (m,1H), 8.59 (m, 1H), 8.40 (m, 1H), 7.42 (m, 1H), 7.34 (m, 2H), 7.24 (m,2H), 7.13 (m, 1H), 6.96 (m, 1H), 5.95 (m, 2H).

Compound I-583

A solution of Intermediate 2 (1 equiv.) in DMF was treated withisocyanatobenzene (2 equiv.) and triethylamine (2 equiv.). The resultingreaction mixture was heated at 100° C. for 18 h. Contents were filtered,and the filtrate was directly purified via reverse phase HPLC to deliverthe desired compound, Compound I-583 (1.0 mg, 4% yield) as a solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 10.20 (m, 1H), 9.10 (m, 1H), 8.62 (m,1H), 7.71 (m, 1H), 7.63 (m, 2H), 7.27 (m, 7H), 7.09 (m, 1H), 7.01 (m,1H), 6.88 (m, 1H), 5.99 (m, 2H).

Compound I-491

To a solution of Intermediate 2 (1 equiv.) in dichloromethane was added(4-fluorophenyl)methanesulfonyl chloride (1 equiv.), followed by DBU (1equiv.). The reaction was stirred at 90° C. for 18 h. The reactionmixture was diluted with water, extracted with dichloromethane (3×),washed with 1N hydrochloric acid solution (2×), dried (sodium sulfate),filtered, and concentrated in vacuo. Purification of the crude materialvia reverse phase HPLC delivered the desired compound, Compound I-491(17.8 mg, 17% yield) as a solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.52 (d, 1H), 8.28 (br. s., 1H), 7.38 (br.s., 1H), 7.30 (dd, 2H), 7.25 (br. s., 1H), 7.14-6.97 (m, 4H), 6.92-6.73(m, 3H), 6.63 (d, 1H), 5.91 (s, 2H), 4.54 (br. s., 2H).

Compound I-495

The title compound was prepared following general procedure B, exceptethanol-1,1,2,2-d4-amine was the amine reactant, and the contents wereheated to 90° C. for 20 h. The contents were cooled to 23° C., andpartitioned between a 1:1 mixture of dichloromethane and 1N HClsolution. The layers were separated, and the aqueous layer was extractedwith dichloromethane (×2), and the organic portions were combined andwashed with brine. The mixture was dried over magnesium sulfate,filtered, and concentrated in vacuo. The crude material was purified viasilica gel chromatography utilizing a 0-10% methanol in dichloromethanegradient to deliver the desired compound, Compound I-495 (120 mg, 74%yield) as a solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.09 (d, 1H), 8.17 (d, 1H), 7.61 (s,1H), 7.51 (s, 1H), 7.33 (d, 1H), 7.14-7.28 (m, 2H), 7.10 (t, 1H), 6.82(s, 1H), 5.90 (s, 2H), 4.74 (br. s., 1H).

Compound I-505

5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine(intermediate described in WO2012/3405 A1; 1 equiv.) was added to asuspension of NaH (1.2 equiv.) in anhydrous THF at 23° C. After stirringfor 30 min at 23° C., a solution of propane-2-sulfonyl chloride (1equiv.) in THF was added to the reaction mixture. Contents were heatedto 70° C. and stirred for an additional 18 h. The reaction mixture wasdiluted with water, extracted with dichloromethane (3×), dried (sodiumsulfate), filtered, and concentrated in vacuo. Purification of the crudematerial via reverse phase HPLC delivered the desired compound, CompoundI-505 (2.9 mg, 6% yield) as a solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 11.59 (br. s., 1H), 9.13 (d, 1H), 8.66(br. s., 1H), 7.45 (s, 1H), 7.38-7.31 (m, 1H), 7.26 (d, 1H), 7.24-7.17(m, 1H), 7.13 (t, 1H), 7.08-7.02 (m, 1H), 5.89 (s, 2H), 4.24 (br. s.,1H), 1.35 (d, 6H).

Compound I-510

To a solution of Intermediate 2 (1 equiv.) in dichloromethane was addedDBU (1 equiv.) followed by methyl 2-(chlorosulfonyl)acetate (1 equiv.).The reaction was stirred at 90° C. for 18 h. The reaction mixture wasdiluted with water, extracted with dichloromethane (3×), washed with 1Nhydrochloric acid solution (2×), dried (sodium sulfate), filtered, andconcentrated in vacuo. Purification of the crude material via reversephase HPLC delivered the desired compound, Compound I-510 (8.3 mg, 12%yield) as a solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 8.52 (d, 1H), 8.37 (d, 1H), 7.40 (s, 1H),7.26-7.22 (m, 1H), 7.08-6.99 (m, 4H), 6.63 (d, 1H), 5.93 (s, 2H), 4.31(s, 2H), 3.71 (s, 3H).

Compound I-521

The title compound was prepared following general procedure B, except3-amino-2,2-difluoropropan-1-ol (1.5 equiv., as the HCl salt) was theamine reactant, 1 equivalent of triethylamine was used, and the contentswere heated to 60° C. for 20 h. The contents were cooled to 23° C., andpartitioned between a 1:1 mixture of dichloromethane and 1N HClsolution. The layers were separated, and the aqueous layer was extractedwith dichloromethane (×2), and the organic portions were combined andwashed with brine. The mixture was dried over Na₂SO₄, filtered, andconcentrated in vacuo. The crude material was purified via silica gelchromatography utilizing a 0-10% methanol in dichloromethane gradient todeliver the desired compound, Compound I-521 (36 mg, 60% yield) as asolid.

¹H-NMR (500 MHz, CDCl₃) δ ppm 8.48 (d, 1H), 8.32 (d, 1H), 7.42 (s, 1H),7.24-7.19 (m, 1H), 7.04-6.97 (m, 3H), 6.60 (d, 1H), 6.05 (br. s., 1H),5.93 (s, 2H), 4.12 (td, 2H), 3.74 (t, 2H).

Compound I-539

To a solution of Compound I-510 (1 equiv.) in THF was added sodiumborohydride (3 equiv.) at 23° C. The reaction mixture was heated to 75°C., methanol (4 equiv.) was added dropwise via syringe, and contentsstirred for 1 h. After cooling to 23° C., reaction was concentrated invacuo, and the resulting crude material was purified via reverse phaseHPLC delivered the desired compound, Compound I-539 (1.5 mg, 27% yield)as a solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.69 (d, 1H), 8.35 (d, 1H), 7.47 (s, 1H),7.19 (d, 1H), 6.96 (s, 3H), 6.89 (d, 1H), 6.84-6.82 (m, 1H), 5.89 (s,2H), 3.92 (t, 2H), 3.66 (t, 2H).

Compound I-610

A solution of Intermediate 1 (1 equiv.) in DMSO was treated withpotassium (cyclopropylsulfonyl)amide (2 equiv.). The resulting reactionmixture was stirred at 23° C. for 16 h. Contents were filtered, and thefiltrate was directly purified via reverse phase HPLC to deliver thedesired compound, Compound I-610 (34 mg, 55% yield) as a solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.66 (d, 1H), 8.35 (d, 1H), 7.37 (s, 1H),7.23-7.11 (m, 1H), 7.02-6.89 (m, 2H), 6.86-6.74 (m, 2H), 5.91-5.77 (m,2H), 3.36-3.26 (m, 1H), 1.35-1.17 (m, 2H), 1.08-0.89 (m, 2H).

Compound I-611

A solution of Intermediate 1 (1 equiv.) in DMSO was treated withpotassium (propylsulfonyl)amide (2 equiv.). The resulting reactionmixture was stirred at 23° C. for 16 h.

Contents were filtered, and the filtrate was directly purified viareverse phase HPLC to deliver the desired compound, Compound I-611 (50mg, 81% yield) as a solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.67 (d, 1H), 8.36 (d, 1H), 7.33 (s, 1H),7.23-7.13 (m, 1H), 7.03-6.89 (m, 2H), 6.87-6.81 (m, 1H), 6.79 (d, 1H),5.91-5.68 (m, 2H), 3.63 (t, 2H), 1.93-1.74 (m, 2H), 0.97 (t, 3H).

Compound I-629

A solution of Intermediate 1 (1 equiv.) in DMSO was treated withpotassium methyl(methylsulfonyl)amide (1 equiv.). The resulting reactionmixture was stirred at 23° C. for 16 h. Contents were filtered, and thefiltrate was directly purified via reverse phase HPLC to deliver thedesired compound, Compound I-629 (8 mg, 33% yield) as a solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.11 (d, 1H), 8.93 (d, 1H), 7.62 (s,1H), 7.34 (d, 1H), 7.28 (d, 1H), 7.24-7.19 (m, 1H), 7.12 (td, 1H), 6.94(td, 1H), 5.92 (s, 2H), 3.49 (s, 3H), 3.37 (d, 3H).

Compound I-475

The title compound was prepared following general procedure C, except(S)-2-acetoxy-3,3,3-trifluoropropanoic acid was the acid reactant (3equiv.), 7 equivalents of triethylamine was used, and 4 equivalents ofT3P was used. The solution was heated to 50° C. for 10 minutes, at whichpoint the solution was diluted with ethyl acetate and water. The layerswere separated and the organic layer was washed with water and saturatedaqueous sodium chloride. The organics were dried over magnesium sulfate,filtered, and the solvent was removed in vacuo. Purification via silicagel chromatography (0-5% methanol in dichloromethane gradient) deliveredthe desired compound, Compound I-475 (98 mg, quantitative yield) as awhite solid.

¹H-NMR (500 MHz, CDCl₃) δ ppm 8.81 (d, 1H), 8.78 (s, 1H), 8.50 (d, 1H),8.15 (d, 1H), 7.51 (s, 1H), 7.25-7.22 (m, 1H), 7.09-7.05 (m, 1H), 7.00(t, 1H), 6.85-6.82 (m, 1H), 6.63 (d, 1H), 6.06 (s, 2H), 5.77 (q, 1H),2.39 (s, 3H).

Compound I-485

The title compound was prepared following general procedure B, except4-aminopyrrolidin-2-one was the amine reactant. After stirring at 90° C.for 16 h, additional water was added to solubilize the reactants. After5 h, the reaction mixture was partitioned between dichloromethane andsaturated aqueous sodium bicarbonate. The layers were separated and theaqueous layer was extracted with dichloromethane. The organics weredried over magnesium sulfate, filtered, and the solvent was removed invacuo. Purification via silica gel chromatography (0-15% methanol indichloromethane gradient) delivered the desired compound, Compound I-485(11 mg, 19% yield) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.76 (s, 1H), 8.11 (d, 1H), 7.46 (s, 1H),7.27 (q, 1H), 7.11-7.07 (m, 1H), 7.03 (t, 1H), 6.93 (s, 1H), 6.83-6.80(m, 1H), 5.96 (s, 2H), 5.11-5.06 (m, 1H), 3.90 (dd, 1H), 3.40 (dd, 1H),2.84 (dd, 1H), 2.51 (dd, 1H).

Compound I-500

A solution of2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-ol(Intermediate described in WO2012/003405 A1; 1 equiv.) and phosphoryltrichloride (20 equiv.) was heated to 60° C. for 1 h, after which timethe phosphoryl trichloride was removed in vacuo. The resulting residuewas dissolved in dioxane and water (2:1 ratio).2-(Aminomethyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (3 equiv.) andtriethylamine (10 equiv.) were added and the resulting solution washeated to 110° C. for 7 d. The solution was partitioned between aqueous1 N hydrochloric acid and dichloromethane. The aqueous layer wasextracted with dichloromethane. The organics were dried over magnesiumsulfate, filtered, and the solvent was removed in vacuo. Purificationvia silica gel chromatography (0-100% (7:1=acetonitrile:methanol) indichloromethane gradient) delivered the desired compound, Compound I-500(16 mg, 21% yield) as a yellow solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.77 (s, 1H), 8.20 (d, 1H), 7.37 (s, 1H),7.29-7.24 (m, 1H), 7.09-7.00 (m, 3H), 6.85 (s, 1H), 6.61 (d, 1H), 5.95(s, 2H), 4.08 (s, 2H).

Compound I-518

The title compound was prepared following general procedure B, except3,3,3-trifluoropropane-1,2-diamine (9 equiv.) was the amine reactant,and 30 equivalents of triethylamine was used. After stirring for 16 h,the crude reaction mixture was partitioned between water and ethylacetate. The aqueous layer was extracted with ethyl acetate. Theorganics were dried over magnesium sulfate, filtered, and the solventwas removed in vacuo. Purification via silica gel chromatography (0-5%methanol in dichloromethane gradient) delivered the desired compound,Compound I-518 (10 mg, 21% yield) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.39 (d, 1H), 8.11 (d, 1H), 7.19 (s, 1H),7.14-7.10 (m, 1H), 6.97-6.93 (m, 1H), 6.89 (t, 1H), 6.81-6.78 (m, 1H),6.52 (d, 1H), 5.90 (s, 2H), 5.57 (br s, 1H), 4.17 (ddd, 1H), 3.51-3.44(m, 1H), 3.34 (ddd, 1H).

Compound I-540

A solution of Compound I-403 (1 equiv.) in dichloromethane was treatedwith diisopropylethylamine (2 equiv.), followed by HATU (1.5 equiv.).After stirring for 20 min, ammonia (3 equiv., 0.5 M solution in dioxane)was added. After 22 h, additional ammonia (3 equiv.) was added. After 4hours, the solution was diluted with aqueous 1N hydrochloric acidsolution and dichloromethane. The layers were separated and the aqueouslayer was extracted with dichloromethane. The organics were dried overmagnesium sulfate, filtered, and the solvent was removed in vacuo.Purification via silica gel chromatography (0-15% methanol indichloromethane gradient) delivered the desired compound, Compound I-540(3 mg, 13% yield) as a yellow film.

¹H-NMR (500 MHz, CDCl₃) δ ppm 8.47 (d, 1H), 8.27 (d, 1H), 7.30 (s, 1H),7.24-7.20 (m, 1H), 7.07-6.98 (m, 2H), 6.91 (m, 1H), 6.80 (br s, 1H),6.59 (d, 1H), 6.10 (d, 1H), 5.97 (d, 1H), 5.92 (d, 1H), 5.84 (quint,1H), 5.74 (br s, 1H).

Compound I-568

A solution of Compound I-418 (1 equiv.), diphenyl phosphorazidate (1.5equiv.), and triethylamine (1.5 equiv.) in toluene was heated to 50° C.for 15 h. The solution was cooled to 23° C. and treated with sodiummethanolate (3 equiv., 0.5 N solution in methanol). After stirring at23° C. for 1 h, saturated aqueous sodium bicarbonate solution was addedand the resulting solution was stirred for an additional 1 h. Thereaction was diluted with water and dichloromethane, and the aqueouslayer was extracted with dichloromethane. The organics were dried overmagnesium sulfate, filtered, and the solvent was removed in vacuo togive the crude product. Purification via silica gel chromatography(0-15% (7:1=acetonitrile:methanol) in dichloromethane gradient)delivered the desired compound, Compound I-568 (11 mg, 52% yield) as awhite solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.76 (d, 1H), 8.21 (d, 1H), 7.49 (s, 1H),7.29-7.24 (m, 1H), 7.12-7.06 (m, 1H), 7.03 (t, 1H), 6.94 (d, 1H), 6.80(t, 1H), 5.97 (s, 2H), 5.67-5.58 (m, 1H), 3.73 (dd, 1H), 3.51 (s, 3H),3.42 (dd, 1H).

Compound I-576

The title compound was synthesized in 2 steps:

Step 1: Synthesis of(S)-1-((2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)-1-oxopropan-2-yl acetate

The intermediate was prepared following general procedure C, except(S)-2-acetoxypropanoic acid was the acid reactant (3 equiv.), 10equivalents of triethylamine was used, and 4 equivalents of T3P wasused. The solution was heated to 50° C. for 16 h, at which point thesolution was diluted with ethyl acetate and water. The layers wereseparated and the organic layer was washed with water and saturatedaqueous sodium chloride. The organics were dried over magnesium sulfate,filtered, and the solvent was removed in vacuo. Purification via silicagel chromatography (0-5% methanol in dichloromethane gradient) deliveredimpure intermediate, which was taken onto the next step without furthermanipulation.

Step 2: Synthesis of Compound I-576

To a solution of(S)-1-((2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-pyrimidin-4-yl)amino)-1-oxopropan-2-ylacetate (1 equiv.) in 4:1=methanol:water was added potassium carbonate(0.5 equiv.) in a single portion. After stirring for 10 min, thereaction solution was acidified with 3N hydrochloric acid solution anddiluted with water and dichloromethane. The layers were separated andthe aqueous layer was extracted with dichloromethane. The organics weredried over magnesium sulfate, filtered, and the solvent was removed invacuo. Purification via silica gel chromatography (0-5% methanol indichloromethane) delivered the desired compound, Compound I-576 (4.5 mg,29% yield) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.77 (m, 1H), 8.71 (d, 1H), 8.14 (d, 1H),7.54 (s, 1H), 7.30-7.26 (m, 1H), 7.11-7.03 (m, 2H), 6.91-6.88 (m, 2H),5.98 (s, 2H), 4.32 (q, 1H), 1.45 (d, 3H).

Compound I-580

The title compound was prepared following general procedure C, except2-methyl-2-(methylsulfonyl)propanoic acid was the acid reactant (3equiv.), 10 equivalents of triethylamine was used, and 4 equivalents ofT3P was used. The solution was heated to 70° C. for 3 h, at which pointthe solution was diluted with ethyl acetate and water. The layers wereseparated and the organic layer was washed with water and saturatedaqueous sodium chloride. The organics were dried over magnesium sulfate,filtered, and the solvent was removed in vacuo. Purification via silicagel chromatography (0-100% ethyl acetate in hexanes gradient) deliveredthe desired compound, Compound I-580 (30 mg, 42% yield) as yellow foam.

¹H-NMR (500 MHz, CDCl₃) δ 9.13 (br s, 1H), 8.78 (d, 1H), 8.48 (d, 1H),8.06 (d, 1H), 7.46 (s, 1H), 7.24-7.19 (m, 1H), 7.06-7.02 (m, 1H),7.00-6.97 (m, 1H), 6.89-6.86 (m, 1H), 6.63 (d, 1H), 6.03 (s, 2H), 3.00(s, 3H), 1.81 (s, 6H).

Compound I-582

The title compound was prepared following general procedure C, except5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine(Intermediate described in a previous patent: WO2012/003405 A1; 1equiv.) was used in place of Intermediate 2,2-methyl-2-(methylsulfonyl)propanoic acid was the acid reactant (3equiv.), 10 equivalents of triethylamine was used, and 4 equivalents ofpropylphosphonic anhydride (T3P, 50 wt % in ethyl acetate) was used.After heating the mixture at 90° C. for 4 hours, the solution wasdiluted with ethyl acetate and water. The layers were separated and theaqueous layer was extracted with ethyl acetate. The organics were washedwith water, dried over magnesium sulfate, filtered, and the solvent wasremoved in vacuo. Purification via silica gel chromatography ((7:1acetonitrile:methanol) in dichloromethane gradient) delivered thedesired compound, Compound I-582 (29 mg, 41% yield) as a white solid.

¹H-NMR (500 MHz, CDCl₃) δ 9.10 (br s, 1H), 8.67 (d, 1H), 8.48 (d, 1H),7.42 (s, 1H), 7.23-7.19 (m, 1H), 7.06-7.02 (m, 1H), 7.10-6.97 (t, 1H),6.86 (t, 1H), 6.63 (d, 1H), 6.02 (s, 2H), 3.02 (s, 3H), 1.82 (s, 6H).

Compound I-587

The title compound was prepared following general procedure C, except2-(methylsulfonyl)propanoic acid was the acid reactant (3 equiv.), 10equivalents of triethylamine was used, and 4 equivalents of T3P wasused. After stirring for 1 h at 70° C., the reaction mixture was dilutedwith ethyl acetate and water. The layers were separated and the aqueouslayer extracted with ethyl acetate. The organics were washed with water,dried over magnesium sulfate, filtered, and the solvent was removed invacuo. Purification via silica gel chromatography (0-5% methanol indichloromethane gradient) delivered the desired compound, Compound I-587(45 mg, 64% yield) as a brown solid.

¹H-NMR (500 MHz, CDCl₃) δ 9.45 (br s, 1H), 8.72 (d, 1H), 8.48 (d, 1H),8.01 (d, 1H), 7.34 (s, 1H), 7.21-7.16 (m, 1H), 7.04-7.01 (m, 1H), 6.92(t, 1H), 6.80-6.77 (m, 1H), 6.65 (d, 1H), 6.00 (s, 2H), 4.14 (q, 1H),3.02 (s, 3H), 1.73 (d, 3H).

Compound I-609

To a solution of potassium ((2,2,2-trifluoroethyl)sulfonyl)amide (2equiv.) in dimethylsulfoxide was added Intermediate 1 (1 equiv.). Afterstirring for 62 h, the solution was diluted with ethyl acetate andaqueous 1N hydrochloric acid solution. The layers were separated and theaqueous layer was extracted with ethyl acetate. The organics were washedwith water and brine, dried over magnesium sulfate, filtered, and thesolvent was removed in vacuo. The crude residue was brought up inmethanol and the resulting solid was filtered and washed with additionalmethanol. The residue was brought up again in methanol and the resultingsolids were filtered and rinsed with methanol to deliver the desiredcompound, Compound I-609 (24 mg, 28% yield) as a solid.

¹H-NMR (500 MHz, DMSO-d₆) δ 9.14 (d, 1H), 8.44 (br s, 1H), 7.51 (s, 1H),7.37-7.31 (m, 1H), 7.24-7.20 (m, 2H), 7.12 (t, 1H), 7.02-6.99 (m, 1H),5.92 (s, 2H), 4.74 (br s, 2H).

Compound I-627

A suspension of2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-ol(Intermediate described in WO2012/003405 A1; 1 equiv.) in phosphoryltrichloride (20 equiv.) was heated to 60° C. for 2 h. After evaporatingto dryness in vacuo, the resulting residue and2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropanamide (3 equiv.) weredissolved in 2:1 mix of dioxane:water and treated with triethylamine (10equiv.). The solution was heated to 110° C. for 38 h. The solution wasdiluted with dichloromethane and 1N hydrochloric acid, layers wereseparated, and the aqueous layer was extracted with dichloromethane. Theorganics were dried over magnesium sulfate, filtered, and the solventwas removed in vacuo. Purification via silica gel chromatography (0-65%(7:1=acetonitrile:methanol) in dichloromethane gradient) providedcontaminated product. The crude product was partitioned between waterand dichloromethane. The layers were separated and the organic layer waswashed with water. The organic layer was dried over magnesium sulfate,filtered, and the solvent was removed in vacuo to deliver the desiredcompound, Compound I-627 (1 mg, 1% yield) as a clear film.

¹H-NMR (500 MHz, CD₃OD) δ 8.78 (s, 1H), 8.17 (d, 1H), 7.42 (s, 1H),7.30-7.26 (m, 1H), 7.11-7.04 (m, 2H), 7.01-6.98 (m, 1H), 6.89 (s, 1H),6.59 (d, 1H), 5.97 (s, 2H), 4.10-4.02 (m, 2H).

Compound I-634

The title compound was prepared following general procedure B, except3-amino-1,1,1-trifluoro-2-methylpropan-2-ol (as the HCl salt, 2 equiv.)was the amine reactant, and 4 equivalents of triethylamine was used.After stirring at 90° C. for 21 h, workup and purification via silicagel chromatography (0-70% ethyl acetate in hexanes gradient) deliveredthe desired compound, Compound I-634 (33 mg, 48% yield) as a whitesolid.

¹H-NMR (500 MHz, CDCl₃) δ ppm 8.48 (m, 1H), 8.22 (d, 1H), 7.27 (s, 1H),7.24-7.19 (m, 1H), 7.05-6.95 (m, 3H), 6.61 (m, 1H), 6.04-5.93 (m, 3H),5.74 (br s, 1H), 4.00 (dd, 1H), 3.81 (dd, 1H), 1.44 (s, 3H).

Compound I-631

The title compound was prepared following general procedure B, except4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3 (2H)-one dihydrochloride(2 equiv) was the amine reactant, and 4 equivalents of triethylamine wasused. After stirring at 90° C. for 1.5 h, workup and purification viasilica gel chromatography (0-15% methanol in dichloromethane gradient)delivered the desired compound, Compound I-631 (9 mg, 14% yield) as awhite solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.79 (d, 1H), 8.22 (d, 1H), 7.50 (s, 1H),7.31-7.27 (m, 1H), 7.13-7.09 (m, 1H), 7.05 (t, 1H), 6.94 (m, 1H),6.85-6.82 (m, 1H), 5.98 (s, 2H), 4.76 (s, 2H), 4.17 (t, 2H), 2.85 (t,2H).

Compound I-328

The title compound was prepared following general procedure C, except1-(trifluoromethyl)cyclopropanecarboxylic acid (2 equiv.) was the acidreactant, 3 equivalents of triethylamine was used, and 3 equivalents ofT3P was used. The solution was stirred at 23° C. for 18 h, at whichpoint the solution was diluted with water and extracted with ethylacetate. The organic phase was washed with water (2×) and saturatedaqueous sodium chloride. The organics were dried over sodium sulfate,filtered, and concentrated in vacuo. Purification of the residue viasilica gel chromatography (ethyl acetate in hexanes) delivered thedesired compound, Compound I-328 (2 mg, 14% yield).

¹H-NMR (400 MHz, CDCl₃) δ ppm 8.73 (d, 1H), 8.57 (br s, 1H), 8.45 (d,1H), 8.02 (d, 1H), 7.45 (s, 1H), 7.19 (m, 1H), 7.02 (m, 1H), 6.96 (m,1H), 6.83 (m, 1H), 6.60 (d, 1H), 6.01 (s, 2H), 1.40 (m, 4H).

Compound I-415 The title compound was prepared following generalprocedure C, except5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine(Intermediate described in a previous patent: WO2012/003405 A1; 1equiv.) was used in place of Intermediate 2,1-(trifluoromethyl)cyclopropanecarboxylic acid (3 equiv.) was the acidreactant, 7 equivalents of triethylamine was used, and 4 equivalents ofT3P was used. After heating at 90° C. for 2 d, the vial was cooled to23° C. and the contents were diluted with ethyl acetate. Contents werewashed with water (3×), brine, then dried over sodium sulfate, filtered,and concentrated via rotary evaporation. Purification of the residue viasilica gel chromatography (ethyl acetate in hexanes) delivered thedesired compound, Compound I-415 (42 mg, 30% yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 8.67 (s, 1H), 8.49 (s, 1H), 8.31 (br s,1H), 7.43 (s, 1H), 7.23 (m, 1H), 7.06 (m, 1H), 6.99 (m, 1H), 6.84 (m,1H), 6.63 (s, 1H), 6.04 (s, 2H), 1.64 (m, 2H), 1.45 (m, 2H).

Compound I-460 The title compound was prepared following generalprocedure C, except5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-amine(Intermediate described in a previous patent: WO2012/003405 A1; 1equiv.) was used in place of Intermediate 2,1-cyanocyclopropanecarboxylic acid (3 equiv.) was the acid reactant, 7equivalents of triethylamine was used, and 4 equivalents of T3P wasused. After heating at 50° C. for 18 h, the vial was cooled to 23° C.and the contents were diluted with ethyl acetate. Contents were washedwith water (3×), brine, then dried over sodium sulfate, filtered, andconcentrated via rotary evaporation. Purification of the residue viasilica gel chromatography (ethyl acetate in hexanes) delivered thedesired compound, Compound I-460 (29 mg, 23% yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 8.61 (s, 1H), 8.50 (br s, 1H), 8.41 (s,1H), 7.34 (s, 1H), 7.14 (m, 1H), 6.97 (m, 1H), 6.91 (m, 1H), 6.77 (m,1H), 6.54 (s, 1H), 5.95 (s, 2H), 1.80 (m, 2H), 1.67 (m, 2H).

Compound I-483

The title compound was synthesized in 2 steps:

Step 1: Synthesis of3-(3-(4-chloro-5-nitropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole

2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-nitropyrimidin-4-ol(Intermediate described in a previous patent: WO2012/003405 A1; 1equiv.) was added to phosphorus oxychloride (22 equiv.) and the mixturewas heated for 4 h at 90° C. Contents were concentrated in vacuo, andthe residue was taken up in ethyl acetate and subsequently washed with10% sodium bicarbonate solution (2×), water (2×), and brine. The organiclayer was dried over sodium sulfate, filtered, and concentrated in vacuoto deliver the desired intermediate,3-(3-(4-chloro-5-nitropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazoleas a tan solid (1.86 g, 96% yield).

¹H-NMR (400 MHz, CDCl₃) δ ppm 9.35 (s, 1H), 8.53 (d, 1H), 7.59 (s, 1H),7.25 (m, 1H), 7.07 (m, 1H), 7.02 (m, 1H), 6.91 (m, 1H), 6.65 (d, 1H),6.08 (s, 2H).

Step 2: Synthesis of Compound I-483

The title compound was prepared following general procedure B, except3-(3-(4-chloro-5-nitropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazolewas used in place of Intermediate 1,2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (1.5 equiv.) was theamine reactant, 3 equivalents of triethylamine was used, and contentswere heated to 30° C. for 1 h as a solution in dioxane:water (3:1). Thereaction was cooled and diluted with ethyl acetate. The organic layerwas washed with water (2×) and brine, then dried over sodium sulfate,filtered, and concentrated in vacuo. The crude material was purified viasilica gel chromatography utilizing a 0-100% ethyl acetate/hexanesgradient to deliver the desired compound, Compound I-483 (77 mg, 73%yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 9.36 (s, 1H), 8.59 (m, 1H), 8.55 (d, 1H),7.64 (br s, 1H), 7.42 (s, 1H), 7.28 (m, 1H), 7.08 (m, 1H), 7.06 (m, 1H),6.64 (d, 1H), 5.98 (s, 2H), 4.27, (d, 2H).

Compound I-484

A solution of Compound I-483 (1 equiv.) in methanol at 23° C. wastreated with 10% palladium on carbon (0.2 equiv.), then placed under anatmosphere of H₂ delivered via a balloon filled with hydrogen attachedto a needle. The mixture was stirred for 1 h under positive H₂ pressure,and filtered through celite. The filter cake was rinsed with methanol,and the combined washes were concentrated in vacuo. The resulting cruderesidue was purified via silica gel chromatography utilizing a ethylacetate in hexanes gradient to deliver the desired compound, CompoundI-484 (53 mg, 66% yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 9.39 (s, 1H), 7.92 (br s, 1H), 7.19 (m,1H), 7.13 (m, 2H), 7.98 (m, 1H), 6.92 (m, 2H), 6.52 (s, 1H), 5.85 (s,2H), 4.01, (s, 2H).

Compound I-541

A mixture of3-(3-(4-chloro-5-nitropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole(as described in step 1 of synthesis of Compound I-483 (1 equiv.),methyl carbamate (5 equiv.) and cesium carbonate (5 equiv.) was heatedat 90° C. for 18 h. After cooling to 23° C., the mixture was dilutedwith ethyl acetate and washed with water (3×) and brine. Contents weredried over sodium sulfate, filtered, and concentrated in vacuo. Theresulting crude residue was purified via silica gel chromatographyutilizing a ethyl acetate/hexanes gradient to deliver the desiredcompound, Compound I-541 (35 mg, 19% yield) as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 10.09 (br s, 1H), 9.51 (s, 1H), 8.50 (d,1H), 7.60 (s, 1H), 7.24 (m, 1H), 7.06 (m, 1H), 7.02 (m, 1H), 6.87 (m,1H), 6.67 (d, 1H), 6.07 (s, 2H), 3.95 (s, 3H).

Compound I-542

A solution of Compound I-541 (1 equiv.) in methanol at 23° C. wastreated with 10% palladium on carbon (0.2 equiv.), then placed under anatmosphere of H₂ delivered via a balloon filled with hydrogen attachedto a needle. The mixture was stirred for 1 h under positive H₂ pressure,and filtered through celite. The filter cake was rinsed with methanol,and the combined washes were concentrated in vacuo. The resulting cruderesidue was purified via silica gel chromatography utilizing a ethylacetate in hexanes gradient to deliver the desired compound, CompoundI-542 (26 mg, 87% yield) as a solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 8.43 (d, 1H), 8.27 (s, 1H), 7.52 (s, 1H),7.32 (s, 1H), 7.18 (m, 1H), 7.02 (m, 1H), 6.99 (m, 1H), 6.77 (m, 1H),6.57 (d, 1H), 5.99 (s, 2H), 4.61 (br s, 2H), 3.81 (s, 3H).

Compound I-488

The title compound was prepared following general procedure B, except2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (2.3 equiv.) was theamine reactant,3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2,3-difluorobenzyl)-1H-pyrazol-5-yl)isoxazole(described in step 2 towards the synthesis of Compound I-235) was usedin place of Intermediate 1, and contents were heated to 90° C. for 3 d.Contents were cooled to 23° C. and the mixture was diluted with ethylacetate. The organic layer was washed with water (2×) and brine, thendried over sodium sulfate, filtered, and concentrated in vacuo. Thecrude material was purified via silica gel chromatography (ethyl acetatein hexanes gradient) to deliver the desired compound, Compound I-488 (62mg, 44% yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 8.52 (s, 1H), 8.39 (s, 1H), 8.29 (s, 1H),7.25 (s, 1H), 7.09 (m, 1H), 6.98 (m, 1H), 6.96 (m, 1H), 6.64 (s, 1H),5.99 (s, 2H), 5.58 (br s, 1H), 4.14 (d, 2H).

Compound I-489

The title compound was prepared following general procedure B, except2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (1.3 equiv.) wasthe amine reactant,3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(2,3-difluorobenzyl)-1H-pyrazol-5-yl)isoxazole(described in step 2 towards the synthesis of Compound I-235) was usedin place of Intermediate 1, and contents were heated to 90° C. for 3 d.Contents were cooled to 23° C. and the mixture was diluted with water,and the pH was adjusted to 5 with 3N HCl solution. The mixture wasfiltered, and the filter cake was washed with water (2×) and dried undervacuum. A portion of the residue dissolved in dichloromethane/methanol(4 mL, 1:1). Filtration left 62 mg of insoluble material. The solublefraction was subjected to silica gel chromatography utilizing adichloromethane/methanol gradient to yield Compound I-489 as a whitesolid (60 mg). Analysis of the insoluble material left from filtrationalso showed to be Compound I-489 (total: 0.122 g, 90% yield).

1H-NMR (400 MHz, CD₃OD) δ ppm 8.77 (d, 1H), 8.16 (d, 1H), 7.51 (s, 1H),7.15 (m, 1H), 7.01 (m, 1H), 6.94 (d, 1H), 6.71 (m, 1H), 6.00 (s, 2H),4.43 (d, 1H), 4.12 (d, 1H).

Compound I-522

A solution of Compound I-489 (1 equiv.) in dichloromethane was treatedwith Hunig's base (3 equiv.) and HATU (1.5 equiv.). The resultingsolution was stirred for 2 h, then a solution of ammonia (0.5 M indioxane, 8 equiv.) was added to the reaction. Contents were allowed tostir overnight at 23° C. The mixture was diluted with dichloromethaneand washed with water (3×) and brine. The solution was then dried oversodium sulfate, filtered, and concentrated in vacuo. Purification of thecrude residue via silica gel chromatography utilizing adichloromethane/methanol gradient delivered the desired compound,Compound I-522 (5 mg, 8% yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 8.45 (s, 1H), 8.14 (s, 1H), 7.98 (s, 1H),7.18 (s, 1H), 7.13 (s, 1H), 7.01 (m, 1H), 6.90 (m, 2H), 6.56 (s, 1H),5.90 (s, 2H), 5.65 (br s, 1H), 5.53 (br s, 1H), 4.12 (d, 2H).

Compound I-507

The title compound was synthesized in 4 steps:

Step 1: Synthesis of (3,3,3-trifluoropropyl)hydrazine hydrochloride

3-Bromo-1,1,1-trifluoropropane (1 equiv.) and hydrazine hydrate (10equiv.) were dissolved in absolute ethanol and heated at 80° C. for 18h. The solution was cooled to 23° C. and concentrated under vacuum at15° C. The thick oil was diluted with water and dichloromethane, thensolid potassium carbonate was added to saturate the aqueous layer. Thephases were mixed and separated, then the aqueous phase was extractedwith additional dichloromethane (2×). The combined organic phases weredried over sodium sulfate, filtered, and concentrated under vacuum togive a colorless oil. A small portion of the neutral hydrazine productwas removed for characterization by NMR. The remainder was taken up indiethyl ether and treated with hydrochloric acid (2.5 M solution inethanol), and the resulting mixture was concentrated in vacuo to deliverthe desired intermediate (3,3,3-trifluoropropyl)hydrazine hydrochloride(2.02 g, 43% yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 3.18 (br s, 4H), 3.02 (m, 2H), 2.36 (m,2H).

Step 2: Synthesis of ethyl3-(isoxazol-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-5-carboxylate

A solution of (3,3,3-Trifluoropropyl)hydrazine hydrochloride (1 equiv.)in a mixture of ethanol and water (9:1) at 23° C. was treated withpotassium carbonate (0.6 equiv.) followed by ethyl4-(isoxazol-3-yl)-2-(methoxy(methyl)amino)-4-oxobut-2-enoate (2 equiv.,generated in step 1 of general procedure A, by using1-(isoxazol-3-yl)ethanone in step 1). The solution was stirred 2 d at23° C., then 6N hydrochloric acid (1.5 equiv.) was added drop wise tothe reaction. Solvents were removed in vacuo, and the residue was takenup in ethyl acetate. The organics were washed with water (5×), brine,dried over sodium sulfate, filtered, and concentrated in vacuo. Thecrude residue was purified via silica gel chromatography utilizing aethyl acetate in dichloromethane gradient to yield the desired pyrazoleester, ethyl3-(isoxazol-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-5-carboxylate(1.34 g, 36% yield) as a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 8.55 (d, 1H), 7.15 (s, 1H), 6.63 (d, 1H),4.95 (m, 2H), 4.46 (q, 2H), 2.85 (m, 2H), 1.44 (t, 3H).

Step 3: Synthesis of5-(isoxazol-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboximidamide

The desired amidine intermediate was generated according to theprocedure described in step 3 of general procedure A, with the exceptionof using ethyl3-(isoxazol-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-5-carboxylate asthe starting ester, and the mixture was heated 4 h at 110° C. Thereaction mixture was cooled in ice, then methanol (14 equiv.) andaqueous hydrochloric acid (17 equiv.) were added in succession over 5min. This mixture was heated 30 min at 80° C., then cooled in ice andfiltered. The filter cake was washed with toluene (2×) and air dried toyield the crude amidine hydrochloride salt. This material was stirred insaturated aqueous sodium carbonate, and was extracted with ethylacetate/isopropyl alcohol (5:1 mix). The organic phase was washed withwater and brine, dried over sodium sulfate, filtered, and concentratedin vacuo to deliver the desired neutral amidine5-(isoxazol-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboximidamideas a light yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 8.45 (d, 1H), 6.99 (s, 1H), 6.55 (d, 1H),5.61 (br. s., 3H), 4.83-4.74 (m, 2H), 2.81-2.65 (m, 2H).

Step 4: Synthesis of Compound I-507

The title product was prepared following step 4 of general procedure A,except5-(isoxazol-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboximidamidewas the starting amidine, 2.5 equivalents of sodium(Z)-3-ethoxy-2-fluoro-3-oxoprop-1-en-1-olate was used, and the mixturewas heated for 2 h at 90° C. The reaction was cooled to 23° C. and thesolvent was removed in vacuo. The residue was redissolved indichloromethane and treated with hydrochloric acid (2.5M in ethanol, 3equiv.). The resulting solids were filtered, washed with dichloromethane(2×), and air dried to deliver the desired compound, Compound I-507(0.43 g, 110% yield) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ ppm 8.84 (d, 1H), 8.03 (d, 1H), 7.40 (s, 1H),6.95 (d, 1H), 4.96 (t, 2H), 2.92 (m, 2H).

Compound I-511

The title compound was synthesized in 2 steps:

Step 1: Synthesis of3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)isoxazole

A mixture of Compound I-507 (1 equiv.) in phosphorus oxychloride (28equiv.) was heated for 2 h at 90° C. The solvent was removed in vacuoand the residue rinsed with dichloromethane (2×) to deliver the desiredintermediate3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)isoxazole(0.28 g, 69% yield) as a tan solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 8.59 (s, 1H), 8.47 (d, 1H), 7.30 (s, 1H),6.60 (d, 1H), 4.92 (t, 2H), 2.81 (m, 2H).

Step 2: Synthesis of Compound I-511

The title compound was prepared following general procedure B, except2-aminoacetamide (as the HCl salt, 2 equiv.) was the amine reactant,3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)isoxazole(described above) was used in place of Intermediate 1, 5 equivalents oftriethylamine was used, and contents were heated to 90° C. for 2 h. Themixture was cooled to 23° C., diluted with water and the pH taken to ˜5with aqueous 3N hydrochloric acid. The crude product was collected byfiltration, then purified via silica gel chromatography utilizing amethanol in dichloromethane gradient to deliver the desired compound,Compound I-511 (12 mg, 45% yield) as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ ppm 8.81 (s, 1H), 8.13 (d, 1H), 7.34 (s, 1H),6.93 (s, 1H), 4.91 (m, 2H), 4.21 (s, 2H), 2.89 (m, 2H).

Compound I-513

3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)isoxazole(described in step 1 of synthesis of Compound I-511 (1 equiv.) andconcentrated aqueous ammonium hydroxide (2.8 equiv.) in dioxane weresealed in a screw-cap vial and heated for 2 h at 95° C. The mixture wascooled to 23° C., diluted with water, then filtered. The filter cake waswashed with water (2×) and air dried to deliver the desired compound,Compound I-513 (0.14 g, 76% yield) as a light tan powder.

¹H-NMR (400 MHz, CDCl₃) δ ppm 8.51 (d, 1H), 8.21 (d, 1H), 7.26 (s, 1H),6.63 (d, 1H), 5.26 (s, 2H), 4.95 (m, 2H), 2.85 (m, 2H).

Compound I-516 and Compound I-517

The title compound was prepared following general procedure B, except2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (2 equiv.) was theamine reactant,3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)isoxazole(described in step 1 of synthesis of Compound I-511 (1 equiv.) was usedin place of Intermediate 1, 6 equivalents of triethylamine was used, andcontents were heated to 95° C. for 3 d. The mixture was cooled to 23° C.and diluted with ethyl acetate, then washed with water (2×) and brine.Contents dried over sodium sulfate, filtered, and concentrated in vacuoto yield the crude product. Residue was purified via silica gelchromatography utilizing a hexane/ethyl acetate gradient to deliver twoproducts, Compound I-516 (27 mg, 37% yield) as a white solid, andCompound I-517 (9 mg, 16% yield) as a white solid.

¹H-NMR for Compound I-516 (400 MHz, CDCl₃) δ ppm 8.56 (s, 1H), 8.40 (s,1H), 8.31 (d, 1H), 7.21 (s, 1H), 6.67 (s, 1H), 5.60 (m, 1H), 4.95 (m,2H), 4.16 (d, 2H), 2.93 (m, 2H).

¹H-NMR for Compound I-517 (400 MHz, CDCl₃) δ ppm 8.54 (s, 1H), 8.15 (d,1H), 7.17 (s, 1H), 6.68 (s, 1H), 4.94 (m, 2H), 3.69 (q, 4H), 2.89 (m,2H), 1.31 (t, 6H).

Compound I-523

The title compound was prepared following general procedure B, except1-((methylamino)methyl)cyclopropanecarboxylic acid (as the HCl salt) wasthe amine reactant,3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)isoxazole(described in step 1 of synthesis of Compound I-511 (1 equiv.) was usedin place of Intermediate 1, 6.6 equivalents of triethylamine was used,and contents were heated to 90° C. for 18 h. The reaction mixture wasdiluted with water and carefully taken to pH 4 with aqueous 3Nhydrochloric acid solution. The mixture was filtered, and the filtercake was washed with water (2×) and air dried to deliver the desiredcompound, Compound I-523 (9 mg, 60% yield) as a white solid.

1H-NMR (400 MHz, CDCl₃) δ ppm 8.51 (d, 1H), 8.16 (d, 1H), 7.16 (s, 1H),6.64 (s, 1H), 4.92 (m, 2H), 4.10 (s, 2H), 3.35 (d, 3H), 2.87 (m, 2H),1.44 (m, 2H), 1.13 (m, 2H).

Compound I-573

The title compound was synthesized in 2 steps:

Step 1: Synthesis of give 3-(methylsulfonyl)propanoic acid

A solution of 3-(methylthio)propanoic acid (1 equiv.) in glacial aceticacid was cooled in ice as aqueous hydrogen peroxide (27%, 6 equiv.) wasadded at a rate to keep the internal temperature <50° C. The coolingbath was removed and stirring was continued for 18 h at 23° C. Thesolvents were removed in vacuo to leave a white paste. The paste wasmixed in dichloromethane and filtered. The filter cake was washed withadditional dichloromethane (3×) and air dried to deliver the desiredcarboxylic acid, 3-(methylsulfonyl)propanoic acid (3.0 g, 47% yield) asa white solid. ¹H-NMR (400 MHz, acetone-d₆) δ ppm 10.2 (br s, 1H), 3.38(t, 2H), 3.00 (s, 3H), 2.85 (t, 2H).

The title compound was prepared following general procedure C, except3-(methylsulfonyl)propanoic acid (2 equiv.) was the acid reactant, 6equivalents of triethylamine was used, and 3 equivalents ofpropylphosphonic anhydride (T3P, 50 wt % in ethyl acetate) was used, andthe solution was heated to 70° C. for 18 h. Contents cooled to 23° C.,diluted with ethyl acetate, then washed with water (3×) and brine.Contents were dried over sodium sulfate, filtered, and concentrated invacuo. Purification of the residue via silica gel chromatographyutilizing an ethyl acetate in hexanes gradient delivered the desiredcompound, Compound I-573 (6 mg, 8% yield) as a white solid.

¹H-NMR (400 MHz, acetone-d₆) δ ppm 8.77 (d, 1H), 8.58 (d, 1H), 7.92 (d,1H), 7.40 (s, 1H), 7.20 (m, 1H), 7.03 (m, 1H), 6.98 (m, 1H), 6.94 (d,1H), 6.83 (m, 1H), 5.88 (s, 2H), 3.38 (t, 2H), 3.07 (t, 2H), 2.88 (s,3H).

Compound I-588

The title compound was synthesized in 6 steps:

Step 1: Synthesis of ethyl3-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutanoate

A solution of ethyl 3-amino-4,4,4-trifluorobutanoate hydrochloride (1equiv.) in THF was cooled in ice as triethylamine (2.2 equiv.) was addedover 5 min. Di-tert-butyl dicarbonate (2 equiv.) in THF was added to thevessel and the mixture was stirred for 2 d at 23° C. The solvent wasremoved in vacuo and the residue was taken up in ethyl acetate, thenwashed sequentially with water, 10% aqueous sodium bicarbonate solution,water (3×), then brine. Contents dried over sodium sulfate, filtered,and concentrated in vacuo. Purification of the residue via silica gelchromatography utilizing a ethyl acetate in hexanes gradient deliveredthe desired Boc protected amine, ethyl3-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutanoate (1.9 g, 74%yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 5.25 (br d, 1H), 4.68 (m, 1H), 4.16 (q,2H), 2.74 (dd, 1H), 2.57 (dd, 1H), 1.43 (s, 9H), 1.25 (t, 3H).

Step 2: Synthesis of tert-butyl(1,1,1-trifluoro-4-hydroxybutan-2-yl)carbamate

A solution of ethyl3-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutanoate (1 equiv.) inTHF was cooled in ice as lithium aluminum hydride (2M in THF, 2.5equiv.) was added over 5 min.

The solution was stirred for 3 h at 23° C., then re-cooled in ice andtreated sequentially with water, 15% aqueous NaOH, and water. Stirringwas continued for 15 min at 23° C., then the mixture was filteredthrough Celite and the filter cake was rinsed with ethyl acetate (4×).The combined organic filtrates were dried over sodium sulfate, filtered,and concentrated in vacuo to deliver the desired alcohol intermediate,tert-butyl (1,1,1-trifluoro-4-hydroxybutan-2-yl)carbamate (0.26 g, 98%yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 4.79 (br d, 1H), 4.44 (m, 1H), 3.76 (m,1H), 3.68 (m, 1H), 2.63 (br s, 1H), 2.08 (m, 1H), 1.55 (m, 1H), 1.45 (s,9H).

Step 3: Synthesis of 3-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutylmethanesulfonate

A solution of tert-butyl (1,1,1-trifluoro-4-hydroxybutan-2-yl)carbamate(1 equiv.) and triethylamine (2.5 equiv.) in dichloromethane was stirredat 23° C. as methanesulfonyl chloride (1.7 equiv.) was added to thevessel. The resulting solution was stirred for 2 h at 23° C., thendiluted with ethyl acetate and washed with water (4×) and brine.Contents were dried over sodium sulfate, filtered, and concentrated invacuo to deliver the desired mesyl-protected alcohol intermediate3-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutyl methanesulfonate(0.29 g, 89% yield) as a colorless solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 4.67 (br d, 1H), 4.45 (m, 1H), 4.31 (m,2H), 3.05 (s, 3H), 2.28 (m, 1H), 1.84 (m, 1H), 1.45 (s, 9H).

Step 4: Synthesis of tert-butyl(1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)carbamate

A solution of 3-((tert-butoxycarbonyl)amino)-4,4,4-trifluorobutylmethanesulfonate (1 equiv.) in THF at 23° C. was treated with sodiummethanethiolate (10 equiv.), and the resulting solution was heated for 6h at 60° C. The reaction mixture was then cooled in ice asm-chloroperoxybenzoic acid (70% wt/wt, 12.5 equiv.) was added inportions. The reaction was assayed by LC/MS to confirm completeconversion to sulfone. The mixture was diluted with ethyl acetate andwashed sequentially with 7:1=10% aqueous bicarbonate/3N aqueous sodiumhydroxide solution (2×), 10% aqueous sodium bicarbonate solution (2×),water (4×), then brine. The contents were dried over sodium sulfate,filtered, and concentrated in vacuo to yield a residue. The crudeproduct was purified via silica gel chromatography, utilizing a ethylacetate in hexanes gradient to deliver the desired sulfone intermediate,tert-butyl (1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)carbamate (0.18g, 72% yield) as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ ppm 4.75 (br d, 1H), 4.36 (m, 1H), 3.16 (m,2H), 2.99 (s, 3H), 2.37 (m, 1H), 2.07 (m, 1H), 1.49 (s, 9H).

Step 5: Synthesis of 1,1,1-trifluoro-4-(methylsulfonyl)butan-2-amine

Tert-butyl (1,1,1-trifluoro-4-(methylsulfonyl)butan-2-yl)carbamate (1equiv.) was dissolved in dichloromethane at 23° C., then treated withtrifluoroacetic acid (25 equiv.) and stirred for 3 h at 23° C. Thereaction was diluted with dichloromethane and 10% aqueous sodiumbicarbonate solution, and the phases were well mixed and separated. Theaqueous phase was extracted with dichloromethane (3×), and the combinedorganic phases were dried over sodium sulfate, filtered, andconcentrated in vacuo to deliver the desired deprotected amineintermediate, 1,1,1-trifluoro-4-(methylsulfonyl)butan-2-amine (18 mg,54% yield) as a colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ ppm 3.25 (m, 2H), 3.15 (m, 1H), 2.89 (s, 3H),2.23 (m, 1H), 1.80 (m, 1H), 1.36 (br s, 2H).

Step 6: Synthesis of Compound I-588

The title compound was prepared following general procedure B, except1,1,1-trifluoro-4-(methylsulfonyl)butan-2-amine (6 equiv.) was the aminereactant, 6 equivalents of triethylamine was used, and contents wereheated via microwave to 215° C. for 2 h as a solution in NMP. Directpurification of the resulting mixture via silica gel chromatographyutilizing an ethyl acetate in hexanes gradient gave impure product.Further purification via reverse phase HPLC delivered the desiredcompound, Compound I-588 (17 mg, 16% yield).

¹H-NMR (400 MHz, CDCl₃) δ ppm 8.40 (d, 1H), 8.23 (d, 1H), 7.29 (s, 1H),7.13 (m, 1H), 6.97 (m, 1H), 6.91 (m, 1H), 6.81 (m, 1H), 6.56 (d, 1H),5.93 (d, 1H), 5.88 (d, 1H), 5.35 (m, 1H), 5.18, (br s, 1H), 3.19 (m,1H), 3.11 (m, 1H), 2.86 (s, 3H), 2.53 (m, 1H), 2.21 (m, 1H).

Compound I-626

The title compound was prepared following general procedure B, except1,1,1-trifluoro-4-(methylsulfonyl)butan-2-amine (1.3 equiv.) was theamine reactant,3-(3-(4-chloro-5-fluoropyrimidin-2-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)isoxazole(described in step 1 of synthesis of Compound I-511 (1 equiv.) was usedin place of Intermediate 1, 1.3 equivalents of triethylamine was used,and contents were heated via microwave to 215° C. for 2.5 h as asolution in NMP. Direct purification of the resulting mixture via silicagel chromatography utilizing an ethyl acetate in hexanes gradient gaveimpure product. Further purification via reverse phase HPLC deliveredthe desired compound, Compound I-626 (1 mg, 1% yield).

¹H-NMR (400 MHz, CDCl₃) δ ppm 8.53 (d, 1H), 8.32 (d, 1H), 7.30 (s, 1H),6.71 (d, 1H), 5.44 (m, 1H), 5.27 (br d, 1H), 4.94 (m, 2H), 3.21 (m, 2H),2.95 (s, 3H), 2.87 (m, 2H), 2.61 (m, 1H), 2.28 (m, 1H).

Compound I-617

The title compound was prepared in 3 steps:

Step 1: Synthesis of diethyl2-(2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-nitropyrimidin-4-yl)-2-methylmalonate

A mixture of3-(3-(4-chloro-5-nitropyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazol-5-yl)isoxazole(described in step 1 towards the synthesis of Compound I-483, 1.2equiv.), diethyl 2-methylmalonate (1 equiv.) and potassium t-butoxide(0.9 equiv.) in THF was stirred at room temperature for 15 min. Thesolution was diluted with saturated aqueous ammonium chloride solutionand ethyl acetate. The phases were separated and the aqueous phase wasextracted twice with ethyl acetate. The combined organic phase waswashed with brine, dried over anhydrous sodium sulfate, filtered, andconcentrated. The crude material was purified via silica gelchromatography (10-50% ethyl acetate in hexane gradient) to deliver thedesired intermediate diethyl2-(2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-nitropyrimidin-4-yl)-2-methylmalonate(94.5 mg, 40% yield) as a yellow solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.56 (s, 1H), 9.14 (d, 1H), 7.69 (s,1H), 7.36 (s, 1H), 7.30 (d, 1H), 7.19-7.25 (m, 1H), 7.12 (t, 1H),6.97-7.03 (m, 1H), 5.95-5.97 (m, 2H), 4.12-4.19 (m, 4H), 1.94 (s, 3H),1.11 (t, 6H).

Step 2: Synthesis of diethyl2-(5-amino-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)-2-methylmalonate

A mixture of diethyl2-(2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-nitropyrimidin-4-yl)-2-methylmalonate(1 equiv.) and 20% Palladium on Carbon (0.5 equiv.) in ethanol and ethylacetate (1:1) was stirred in a hydrogen atmosphere at 23° C. for 18 h.The reaction mixture was then filtered through celite, and the residuewas washed with ethyl acetate. The filterate was concentrated in vacuo,and the residue was carried forward to the next step without any furtherpurification or characterization.

Step 3: Synthesis of Compound I-617

A solution of diethyl2-(5-amino-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-pyrimidin-4-yl)-2-methylmalonatein ethanol and THF (2:1) was heated at 85° C. for 16 h. The resultantsolution was concentrated in vacuo, and the residue was purified viareverse phase HPLC (20-60% acetonitrile in water gradient, with 1% TFA)to deliver the desired compound, Compound I-617 (12 mg, 20% yield) as apale yellow solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.26 (s, 1H), 9.07 (d, 1H), 8.44 (s,1H), 7.57 (s, 1H), 7.30 (d, 2H), 7.17-7.25 (m, 1H), 7.06-7.13 (m, 1H),6.80-6.88 (m, 1H), 5.88-5.99 (m, 2H), 4.01-4.20 (m, 2H), 1.60 (s, 3H),1.05 (s, 3H).

Compound I-618

The title compound was prepared in 2 steps:

Step 1: Synthesis of diethyl 2-(dicyanomethyl)-2-methylmalonate

A mixture of diethyl 2-bromo-2-methylmalonate (1 equiv.), malononitrile(1 equiv.) and potassium t-butoxide (1 equiv.) in THF was heated toreflux for 15 h. The mixture was diluted with ethyl acetate andsaturated aqueous ammonium chloride solution, and the phases wereseparated. The aqueous phase was extracted twice with ethyl acetate. Thecombined organic phase was washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated in vacuo to give an oil. Theoil was purified via silica gel chromatography, utilizing a 10-15% ethylacetate in hexane gradient to deliver the desired intermediate, diethyl2-(dicyanomethyl)-2-methylmalonate (5.76 g, 32% yield) as a colorlessoil.

¹H NMR (500 MHz, CDCl₃) δ ppm 4.53 (s, 1H), 4.27-4.39 (m, 4H), 1.81 (s,3H), 1.33 (t, 6H).

Step 2: Synthesis of Compound I-618

A mixture of5-(isoxazol-3-yl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-3-carboximidamide(generated in step 3 towards the synthesis of Compound I-507 (1 equiv.),diethyl 2-(dicyanomethyl)-2-methylmalonate (1.15 equiv.) and potassiumbicarbonate (2 equiv.) in t-BuOH was heated to reflux for 5 h. Theresultant solution was then concentrated in vacuo, and the residue waspurified via silica gel chromatography utilizing a 0-5% methanol indichloromethane gradient to deliver the desired compound, Compound I-618(88.5 mg, 51% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.31 (s, 1H), 9.14 (d, 1H), 7.34 (s,1H), 7.24 (d, 1H), 6.57-6.71 (m, 2H), 4.85 (t, 2H), 4.11 (t, 2H),2.85-2.98 (m, 2H), 1.61 (s, 3H), 1.12 (t, 3H).

Compound I-619

Ammonia (7.0 M in MeOH, 200 equiv.) was added to Compound I-618 (1equiv.). The reaction mixture was heated at 50° C. for 16 h. Theresultant solution was then concentrated in vacuo, and the residue waspurified via reverse phase HPLC (20-40% acetonitrile in water gradient,with 1% TFA) to deliver the desired compound, Compound I-619 (4.7 mg,31% yield) as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.30 (s, 1H), 9.14 (d, 1H), 7.42-7.50(m, 1H), 7.36 (s, 1H), 7.25 (d, 1H), 7.17-7.22 (m, 1H), 6.67-6.92 (m,2H), 4.83-4.89 (m, 2H), 2.86-2.99 (m, 2H), 1.56 (s, 3H).

Compound I-620

The title compound was prepared in 3 steps:

Step 1: Synthesis of(E)-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine

A mixture of1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamide(generated in step 3 towards the synthesis of Compound I-507 (1 equiv.),(E)-2-(phenyldiazenyl)malononitrile (1.2 equiv.) and potassiumbicarbonate (2 equiv.) in t-BuOH was heated to reflux for 18 h. Aftercooling, the reaction mixture was concentrated in vacuo, and carriedforward to the next step without any further purification.

Step 2: Synthesis of2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-pyrimidine-4,5,6-triamine

A mixture of(E)-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-(phenyldiazenyl)pyrimidine-4,6-diamine (1 equiv.) and 20% palladium on carbon (0.5equiv.) in DMF was stirred under a hydrogen atmosphere at 23° C. for 18h. The reaction mixture was then filtered through celite and the residuewas washed with DMF followed by a small portion of methanol. Thefiltrate was concentrated in vacuo, and the residue was suspended inethyl acetate and a drop of methanol and stirred vigorously. Theprecipitate was filtered, washed with ethyl acetate, and dried undervacuum to deliver the desired triaminopyrimidine intermediate,2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-pyrimidine-4,5,6-triamine(278 mg, 46% yield over 2 steps) as a dark yellow solid.

Step 3: Synthesis of Compound I-620

A solution of 2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidine-4,5,6-triamine (1 equiv.) in pyridine at 0° C. was treatedwith methyl chloroformate (1 equiv.). The reaction mixture was slowlywarmed to 23° C. and stirred for 18 h. Volatiles were removed in vacuo,and the residue was dissolved in ethyl acetate and washed with water.

Contents were dried over anhydrous sodium sulfate, filtered, andconcentrated to give a dark yellow solid. The crude material waspurified via reverse phase HPLC (20-40% acetonitrile in water gradient,with 1% TFA) to deliver the desired compound, Compound I-620 (15 mg, 26%yield) as a pale yellow solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.82 (d, 1H), 7.51 (s, 1H), 7.27-7.35 (m,1H), 7.04-7.15 (m, 2H), 6.92-6.99 (m, 1H), 6.89 (d, 1H), 6.00 (s, 2H),3.78 (br. s., 3H), 3.34-3.35 (m, 1H).

Compound I-621

A solution of Compound I-620 (1 equiv.) and LiHMDS (1M in toluene, 6equiv.) in THF at 0° C. was stirred for 20 min. Iodomethane (12 equiv.)added to the reaction vessel, and mixture was warmed to 23° C. andstirred for 1 h. The mixture was diluted with dichloromethane andsaturated aqueous ammonium chloride solution, and the phases wereseparated. The aqueous phase was extracted twice with dichloromethane.The combined organic phases were dried over anhydrous magnesium sulfate,filtered, and concentrated. The crude material was purified via reversephase HPLC (20-40% acetonitrile in water gradient, with 1% TFA) todeliver the desired compound, Compound I-621 (1.6 mg, 17% yield) as ayellow solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.83 (d, 1H), 7.53 (s, 1H), 7.27-7.35 (m,1H), 7.05-7.15 (m, 2H), 6.96 (t, 1H), 6.90 (d, 1H), 6.00 (s, 2H),3.66-3.86 (m, 3H), 3.13 (d, 3H).

Compound I-623

The title compound was prepared in 2 steps:

Step 1: Synthesis of4-amino-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carbohydrazide

A mixture of Compound I-420 (1 equiv.), anhydrous hydrazine (325equiv.), and water (11.2 equiv.) in methanol was heated at 50° C. for 2h. The resultant solution was concentrated in vacuo. Excess hydrazinewas azeotropically removed by treatment with methanol anddichloromethane to deliver the desired acyl hydrazine intermediate,4-amino-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carbohydrazideas a yellow solid. The material was used as-is in the next step withoutfurther purification.

Step 2: Synthesis of Compound I-623

A mixture of4-amino-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carbohydrazide(1 equiv.) and N-acetyl imidazole (4 equiv.) in THF was stirred at 23°C. for 16 h. The resultant solution was concentrated in vacuo, and theresidue was purified via reverse phase HPLC (20-80% acetonitrile inwater gradient, with 1% TFA) to deliver the desired compound, CompoundI-623 (71 mg, 46% yield) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.80 (d, 1H), 7.52 (s, 1H), 7.25-7.32 (m,1H), 7.06-7.14 (m, 1H), 7.01-7.06 (m, 1H), 6.87-6.92 (m, 2H), 5.98 (s,2H), 2.66 (s, 1H), 2.00 (s, 3H), 1.82 (s, 3H).

Compound I-478

To a stirred solution of Compound I-461 (1 equiv.) in DMF and ethanol(3:2) was added 10% palladium on carbon (10 equiv.), and the reactionvessel was placed under a hydrogen atmosphere via a balloon and needle.Contents stirred for 18 h at 23° C., and the mixture was filtered andconcentrated in vacuo. The crude material was purified via reverse phaseHPLC to deliver the desired compound, Compound I-461 (5 mg, 19% yield)as a solid.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 9.69 (s, 1H), 9.11 (d, 1H), 8.78 (d,1H), 8.00 (d, 1H), 7.72 (s, 1H), 7.31-7.38 (m, 1H), 7.29 (d, 1H),7.21-7.26 (m, 1H), 7.12 (t, 1H), 6.86-6.94 (m, 2H), 5.95 (s, 2H),1.22-1.28 (m, 2H), 1.09-1.14 (m, 2H).

Compound I-479

To a stirred solution of Intermediate 2 (1 equiv.) and2-methoxyethanesulfonyl chloride (1 equiv.) in dichloromethane was addedDBU (1 equiv.). The reaction was heated to 60° C. for 24 h, then cooledto 23° C. Contents diluted in water and extracted with dichloromethane(3×). The combined organic layers were washed with 1N HCl solution,dried over sodium sulfate, filtered, and concentrated in vacuo. Thecrude material was purified via reverse phase HPLC to deliver thedesired compound, Compound I-479 (8 mg, 6% yield) as a solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.82 (d, 1H), 8.50 (d, 1H), 7.60 (s, 1H),7.27-7.35 (m, 1H), 7.05-7.15 (m, 3H), 6.94-6.98 (m, 2H), 6.02 (s, 2H),3.86 (s, 4H), 3.27 (s, 3H).

Compound I-595

A solution of2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-5-amine(this compound was described in previous patent application WO2012003405A1) in dichloromethane/pyridine (2:1) was treated with3,3,3-trifluoropropane-1-sulfonyl chloride (1.8 equiv.). After 3 h, 1NNaOH solution was added and the reaction was stirred for 1.5 h. Waterwas then added and the resultant mixture was acidified to pH 3 with 1NHCl solution and extracted with dichloromethane. The organic phases weredried over sodium sulfate, filtered and the solvent was removed invacuo. The crude material was purified via silica gel chromatographyutilizing a 0-10% methanol/dichloromethane gradient to deliver thedesired compound, Compound I-595 (6.8 mg, 15% yield) as a white solid.

¹H-NMR (500 MHz, CD₃OD) δ ppm 8.77 (d, 1H), 8.74 (s, 2H), 7.52 (s, 1H),7.27 (app. q, 1H), 7.09 (m, 1H), 7.04 (app. t, 1H), 6.90 (d, 1H), 6.87(m, 1H), 5.97 (s, 2H), 3.49 (m, 2H), 2.77 (m, 2H).

Compound I-530 and Compound I-531

Compound I-405 was resolved by SFC chiral separation with chiralcel AD-H50 mm×250 mm semi-prep column, using a 15:85 ethanol+0.5%diethylamine:CO₂. Collection of the two peaks and concentration in vacuoyielded Compound I-530 (first peak eluting by analytical HPLC, ChiralcelAD-H 4.6 mm×250 mm, 15:85 ethanol+0.5% diethylamine:hexane) as a lightorange solid. Collection of the peak that eluted second andconcentration in vacuo yielded Compound I-531 (second peak eluting byanalytical HPLC, Chiralcel AD-H 4.6 mm×250 mm, 15:85 ethanol+0.5%diethylamine:hexane) as a light orange solid.

¹H-NMR for Compound I-530 (500 MHz, DMSO-d₆) δ ppm 9.11 (d, 1H), 8.32(d, 1H), 7.93 (t, 1H), 7.90 (s, 1H), 7.78 (br s, 1H), 7.69 (br s, 1H),7.51 (s, 1H), 7.35-7.31 (m, 1H), 7.22-7.19 (m, 2H), 7.10 (t, 1H),7.00-6.97 (m, 1H), 5.90 (s, 2H), 4.02-3.94 (m, 2H).

¹H-NMR for Compound I-531 (500 MHz, DMSO-d₆) δ ppm 9.11 (d, 1H), 8.33(d, 1H), 7.93 (t, 1H), 7.90 (s, 1H), 7.78 (br s, 1H), 7.69 (br s, 1H),7.52 (s, 1H), 7.35-7.31 (m, 1H), 7.22-7.19 (m, 2H), 7.10 (t, 1H),7.00-6.97 (m, 1H), 5.90 (s, 2H), 4.02-3.94 (m, 2H).

Compound I-630

The title compound was synthesized in 2 steps:

Step 1: Synthesis of methyl(2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-5-yl)carbamate

To a solution of2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-5-amine(this compound was described in patent application publicationWO2012003405 A1) (1 equiv.) in anhydrous pyridine at 0° C. was addedmethyl chloroformate (1.2 equiv.). After stirring for 10 min, thereaction mixture was warmed to ambient temperature and monitored closelyby LC/MS. Additional portions of methyl chloroformate (3.2 equiv.) wereadded at 0° C. After stirring at ambient temperature for 20 h, the crudemixture was diluted with water. The resultant tan solids were collectedby filtration and used in the next step without further purification.

Step 2: Synthesis of Compound I-630

A suspension of methyl(2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-5-yl)carbamate(1 equiv.) in DMF at 0° C. was treated with sodium hydride (60% w/w inmineral oil, 1.1 equiv.) and warmed to ambient temperature. After 30min, the reaction mixture was cooled to 0° C. and iodomethane (1.1equiv.) was added. After 25 min, the crude reaction mixture was pouredinto water and extracted with ethyl acetate. The combined organic phaseswere dried over sodium sulfate, filtered and the solvent was removed invacuo. The crude material was purified via silica gel chromatographyutilizing a 20% acetonitrile/methanol (7:1) in dichloromethane gradientto deliver the desired compound, Compound I-630 (12 mg, 21% yield overtwo steps) as a white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm 8.88 (s, 2H), 8.77 (d, 1H), 7.55 (s, 1H),7.28 (app. q, 1H), 7.09 (app. t, 1H), 7.04 (app. t, 1H), 6.91 (d, 1H),6.88 (app. t, 1H), 5.99 (s, 2H), 3.79 (s, 3H), 3.40 (s, 3H).

Example 2A: Biological Activity Measurement by the sGC-HEK-cGMP Assay(Assay Run with SNP Incubation)

Human embryonic kidney cells (HEK293), endogenously expressing solubleguanylate cyclase (sGC), were used to evaluate the activity of testcompounds. Compounds stimulating the sGC receptor should cause anincrease in the intracellular concentration of cGMP. HEK 293 cells wereseeded in Dulbecco's Modification of Eagle's Medium supplemented withfetal bovine serum (10% final) and L-glutamine (2 mM final) in a 200p Lvolume at a density of 1×10⁵ cells/well in a poly-D-lysine coated 96well flat bottom plate and grown overnight at 37° C. Medium wasaspirated and cells were washed with 1× Hank's Buffered Saline SaltSolution (200 μL). Cells were then incubated for 15 minutes at 37° C.with 200P L of a 0.5 mM 3-isobutyl-1-methylxanthine (IBMX) solution.Test article and sodium nitroprusside solutions (x μM concentration fortest article solution and 10 μM concentration for SNP solution; whereinx is one of the following concentrations: 30 μM, 10 μM, 3 μM, 1 μM, 0.3μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM, 0.0003 μM or 0.0001μM) were then added to the assay mixture (2 μL each) and the resultingmixture incubated at 37° C. for 10 minutes. After the 10 minuteincubation, the assay mixture was aspirated and 0.1M HCl (200 μL) wasadded to the cells. The plate was incubated at 4° C. for 30 minutes inthe 0.1M HCl to stop the reaction and lyse the cells. The plates werethen centrifuged at 1,200 g for 5 minutes at room temperature.Supernatants were collected and transferred to a new flat bottom 96 wellplate for analysis by HPLC-MS. Vehicle controls were carried out usingDMSO (1%) solutions. A known sGC stimulator, BAY 41-2272, was used asthe positive control. Samples were diluted with an equal volume of 1 MAmmonium Acetate (pH 7) to neutralize samples for better chromatography.A 2×cGMP standard solution was prepared in 0.1 M HCl and then dilutedwith an equal volume of 1 M Ammonium Acetate, with the following finalconcentrations in nM: 1024, 512, 256, 128, 64, 32, 16, 8, 4, 2, 1. cGMPconcentrations in the test plates were determined from each sample usingthe LC/MS conditions shown in Table 2 below and the calculated cGMPstandard curve. EC₅₀ values were calculated from concentration-responsecurves generated with GraphPad Prism Software. Data were normalized to ahigh control using the following equation: 100*(Sample−LowControl)/(High Control−Low Control), where the low control is theaverage of 6 samples treated with 1% DMSO, and the high control is theaverage of 8-12 samples treated with 10 uM BAY 41-2272. Data were fitusing a non-linear regression, sigmoidal dose response, 3 parameterfits. Samples were typically run in n=1, but for samples that were runwith n=2 (or more) the results given herein correspond to thearithmeticmean of the various results obtained for each given compound. If a curvedid not plateau, then it was constrained to 100% Compounds failing toelicit a minimum response of 30% were reported as ND and EC50 valueswere not determined. The biological activities of some of the compoundsof Formula I and Formula I′ determined with the sGC-HEK assay with SNPincubation are summarized in Table 3.

TABLE 2 (HPLC LC/MS experimental conditions) MS: Thermo Quantum orWaters LCMS Ion Mode: ESI⁺ Scan Type: MRM Dwell Collision Retention TimeEnergy Tube Time Compound: Transition (msec) (V) Lens (min) cGMP 346 >152 100 28 139 1.0 HPLC: Agilent Technologies 1200 Series with CTCAnalytics HTS PAL Column: Thermo Hypersil Gold 2.1 × 50 mm 5 micronparticle size Flow Rate: 400 uL/min Column RT Temperature: Autosampler6° C. Temperature: Injection Volume: 20 uL Mobile Phases: A = 98:2Water:Acetonitrile + 0.1% Formic Acid B = 2:98 Water:Acetonitrile + 0.1%Formic Acid Gradient: Time (min) % A % B 0 100 0 0.3  30 70  2.00  3070  2.01 100 0 4 100 0

TABLE 3 Whole cell activity in the HEK assay with LC/MS detection. HEKassay HEK assay HEK assay Emax - EC50 - EC50 - Compound unconstrainedunconstrained constrained No. (%)⁺ (μM)^(#) (μM)^(#) I-1 E C I-2 E B I-3E B I-4 E C I-6 D C I-7 D D I-8 E B I-9 F B I-10 F B I-11 C I-12 G DI-13 E B I-14 F I-16 G A I-17 E B I-18 E B I-19 D I-20 E B I-21 D B I-22E B I-24 D B I-25 D C I-26 E B I-27 E C I-28 E D I-30 F B I-31 E C I-32E B I-33 E B I-34 D C I-35 D C I-36 D D I-37 E D I-38 E E I-39 E E I-40E D I-41 E D F I-42 F B I-43 E A I-45 D D I-46 E D I-47 D B I-48 E DI-51 D I-52 E D I-53 D I-54 B I-55 D I-56 F B I-57 F B I-58 E B I-59 FI-60 G C I-61 F C I-62 E B I-63 E B I-64 F A I-65 E C I-66 E B I-67 F EF I-68 E E I-69 F C B I-70 F B I-71 E B I-72 E B I-73 D E I-74 D D I-75E B I-76 E C I-77 E A I-78 D B I-79 D B I-80 F C I-81 F I-82 E B I-83 FI-84 E C I-85 F I-86 F B I-87 E B I-88 E D I-89 E A I-90 D E I-91 D EI-92 E D I-94 E D I-95 E I-96 F I-97 E A I-98 D D I-99 E D I-101 E I-102E D I-103 F A I-104 C D I-105 D B I-108 E I-109 E B I-110 C F I-111 FI-112 C D I-113 E C I-114 D D I-115 D A I-116 E B I-117 D D I-118 F DI-119 D B I-120 E B I-121 E B I-123 E B I-124 E A I-125 D A I-126 CI-127 F I-129 B I-133 F I-135 F I-137 F B I-138 D I-139 F B I-140 F DI-141 E B I-142 F A I-143 F B I-144 F C I-145 F D I-146 F B I-148 F BI-149 F I-150 D B I-151 E C I-152 F A I-153 E B I-154 E B I-155 E BI-156 F B I-157 E B I-158 E A I-159 F I-160 F B I-161 F A I-162 F AI-163 F I-452 F B I-165 F I-166 D B I-167 F A I-168 E B I-169 E B I-170E B I-171 E A I-172 F I-173 E B I-174 E C I-175 G A I-176 D D I-177 E BI-178 D E I-179 F B I-180 F D I-181 G C I-182 F A I-183 E B I-184 F CI-185 G D I-186 F A I-188 D I-189 E B I-190 E D I-191 F I-192 H A I-193E D I-194 F B I-195 E A I-196 F B I-197 F D I-198 D A I-199 E E I-200 FE D I-201 G B I-202 F B I-203 D B I-204 F I-205 E C I-206 F I-207 G CI-208 F A I-209 F C I-210 G A I-211 H D I-212 H C I-213 H C I-214 H BI-215 D D I-216 D B I-217 E B I-218 D D I-219 C F I-221 A F I-223 D DI-224 E D I-225 F A I-226 E A I-227 C B I-228 A F I-229 C F I-230 D FI-231 D F I-232 F D I-233 E B I-234 F B I-235 G A I-236 G B I-237 E BI-238 E B I-239 E A I-240 E C I-241 F B I-242 G B I-243 F A I-244 F CI-245 B I-246 D D I-187 F A I-274 G A I-273 E C I-275 F A I-286 F AI-247 F A I-248 F A I-287 F B I-288 F B I-299 D D I-300 E C I-301 E DI-276 D B I-249 E D I-250 F A I-298 E B I-289 E B I-290 E B I-272 E BI-251 E B I-277 E B I-252 E A I-253 E A I-278 F B I-254 F A I-255 F AI-279 F B I-256 F B I-257 F I-280 G B I-292 F A I-285 G A I-258 G DI-259 G B I-305 A F I-306 F A I-307 G D I-361 A B I-364 F A I-365 F DI-366 D A I-367 E A I-368 C B I-369 E A I-371 B F I-372 E B I-374 G BI-375 G B I-376 G E I-453 A D I-454 C F I-455 F A ⁺Code definitions forthe sGC enzyme activity values, expressed as % E_(max) in the presenceof 10 μM of SNP (wherein E_(max) = 100% was the activity in the HEKassay obtained with the positive control BAY 41-2272 at 10 μM in thepresence of 100 μM SNP) are: A = 0 to <10% B = 10 to <20% C = 20 to <40%D = 40 to <60 E = 60 or <80% F = 80 to <100% G = 100 to <120% H = 120%or higher — = not determined ⁺The same code definitions apply for Emaxunconstrained, wherein this value is defined as the maximum activityvalue obtained from the full concentration-response curve for thecompound, relative to the positive control value of 100% obtained asabove. Here, the term “unconstrained” means that, during analysis of thesGC enzyme activity data, the top portion of the concentration-responsecurve was not fitted to 100%. ^(#)EC₅₀ values were obtained from thefull concentration response curve following two methods: EC50constrained refers to the value obtained when the top of the curve wasfitted to 100% (wherein E_(max) = 100% was the activity in the HEK assayobtained with the positive control BAY 41-2272 at 10 μM in the presenceof 100 μM SNP); EC₅₀ unconstrained here reported refer to the valueobtained from a full concentration-response curve when the top of thecurve is not 100%. The EC50 code definitions in micromolar (μM) are:0.001 ≤ EC50 < 0.1 = A 0.1 ≤ EC50 < 0.5 = B 0.5 ≤ EC50 < 1.0 = C 1.0 ≤EC50 < 5.0 = D 5.0 ≤ EC50 < 10.0 = E EC50 ≥ 10.0 = F

Example 2B: Biological Activity Measurement by the sGC-HEK-cGMP Assay(Using HTRF Detection) (Assay Run with SNP Incubation)

Human embryonic kidney cells (HEK293), endogenously expressing solubleguanylate cyclase (sGC), were used to evaluate the activity of testcompounds. Compounds stimulating the sGC enzyme should cause an increasein the intracellular concentration of cGMP. HEK 293 cells were seeded inDulbecco's Modification of Eagle's Medium supplemented with fetal bovineserum (10% final) and L-glutamine (2 mM final) in a 200 μL volume at adensity of 1×10⁵ cells/well in a poly-D-lysine coated 96 well flatbottom plate and grown overnight at 37° C. Medium was aspirated andcells were washed with 1× Hank's Buffered Saline Salt Solution (200p L).Cells were then incubated for 15 minutes at 37° C. with 200 μL of a 0.5mM 3-isobutyl-1-methylxanthine (IBMX) solution. Test article and sodiumnitroprusside solutions were then added to the assay mixture (2 μL each)and the resulting mixture incubated at 37° C. for 10 minutes. After the10 minute incubation, the assay mixture was aspirated and 0.1M HCl (200μL) was added to the cells. The plate was incubated at 4° C. for 30minutes in the 0.1M HCl to stop the reaction and lyse the cells. Theplates were then centrifuged at 1,200 g for 5 minutes at roomtemperature. GMP levels were determined using a cGMP HTRF assay (CisbioProduct #62GM2PEC). For each sample, 5 uL of HEK assay supernatant wasdiluted 1:5 in HTRF kit assay diluent and transferred to a well of theassay plate, and the HTRF assay was performed according to the HTRF kitmanufacturer's instructions. Sample calculations were performed usinghigh and low controls, where high control was supernatant from HEK assayperformed in the presence of 10 uM Bay 41-2272+100 uM SNP, and the lowcontrol was the supernatant from the HEK assay performed in the presenceof vehicle. A cGMP standard solution was prepared in 0.1 M HCl anddiluted in order to perform a cGMP standard curve using the HTRF assay.Using Mean Ratio data from the HTRF assay, sample date were normalizedaccording to the equation: 100*(Sample−Low Control)/(High Control−LowControl). Data were fit to a 3-parameter log agonist dose response (Top(% EMax), Bottom, log EC50) using Graphpad (Prism Software). Data inTable 4 was obtained using this modified assay procedure. (x Mconcentration for test article solution and 10 μM concentration for SNPsolution; wherein x is one of the following concentrations: 30 μM, 10μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, 0.003 μM, 0.001 μM,0.0003 μM and 0.01 nM.

TABLE 4 Whole cell activity in the HEK assay with HTRF detection. HEKassay HEK assay Emax - EC50 - Compound unconstrained unconstrained No.(%)⁺ (μM)^(#) I-3 F A I-16 G A I-29 D B I-36 F B I-51 F C I-67 E D I-161F B I-200 G D I-221 G D I-248 F A I-249 G C I-253 F A I-271 F A ⁺Codedefinitions for the sGC enzyme activity values, expressed as % E_(max)in the presence of 10 μM of SNP (wherein E_(max) = 100% was the activityin the HEK assay obtained with the positive control BAY 41-2272 at 10 μMin the presence of 100 μM SNP) are: A = 0 to <10% B = 10 to <20% C = 20to <40% D = 40 to <60 E = 60 or <80% F = 80 to <100% G = 100 to <120% H= 120% or higher — = not determined ⁺The same code definitions apply forEmax unconstrained, wherein this value is defined as the maximumactivity value obtained from the full concentration-response curve forthe compound, relative to the positive control value of 100% obtained asabove. Here, the term “unconstrained” means that, during analysis of thesGC enzyme activity data, the top portion of the concentration-responsecurve was not fitted to 100%. ^(#)EC₅₀ values were obtained from thefull concentration response * these samples were undiluted. 0.001 ≤ EC₅₀< 0.1 = A 0.1 ≤ EC₅₀ < 0.5 = B 0.5 ≤ EC₅₀ < 1.0 = C 1.0 ≤ EC₅₀ < 5.0 = D5.0 ≤ EC₅₀ < 10.0 = E EC₅₀ ≥ 10.0 = F

Compounds I-306 to I-455 were tested in this assay with the majority ofthem displaying EC₅₀ values of less than 5.0 μM, with E_(max) values ofat least 80%.

Example 2C: Biological Activity Measurement by the sGC-HEK-cGMP Assay,New Protocol with LC/MS Detection

Human embryonic kidney cells (HEK293), endogenously expressing solubleguanylate cyclase (sGC), were used to evaluate the activity of testcompounds. Compounds stimulating the sGC enzyme should cause an increasein the intracellular concentration of cGMP. HEK 293 cells were seeded inDulbecco's Modification of Eagle's Medium supplemented with fetal bovineserum (10% final) and penicillin (100 U/mL)/streptomycin (100 μg/mL) ina 50 μL volume at a density of 1.5×10⁴ cells/well in a poly-D-lysinecoated 384 well flat bottom plate. Cells were incubated overnight at 37°C. in a humidified chamber with 5% CO₂. Medium was aspirated and cellswere washed with 1× Hank's Buffered Saline Salt Solution (50 μL). Cellswere then incubated for 15 minutes at 37° C. with 50 μL of a 0.5 mM3-isobutyl-1-methylxanthine (IBMX) solution. Test article andDiethylenetriamine NONOate (DETA-NONOate) solutions (x M concentrationfor test article solution and 10 μM concentration for DETA-NONOatesolution; wherein x is one of the following concentrations);

30000 nM 7500 nM 1875 nM 468.75 nM 117.19 nM 29.29 nM 7.32 nM 1.83 nM0.46 nM 0.114 nM 0.029 nM

were then added to the assay mixture and the resulting mixture incubatedat 37° C. for 20 minutes. After the 20 minute incubation, the assaymixture was aspirated and 10% acetic acid containing 150 ng/mL+3-cGMP(internal standard for LCMS) (50 μL) was added to the cells. The platewas incubated at 4° C. for 30 minutes in the acetic acid solution tostop the reaction and lyse the cells. The plates were then centrifugedat 1,000 g for 3 minutes at 4° C. and the supernatant transferred to aclean reaction plate for LCMS analysis.

cGMP concentrations were determined from each sample using the LCMSconditions below (Table 5) and calculated standard curve. The standardcurve was prepared in 10% acetic acid with 150 ng/mL+3cGMP (isotopicallylabelled cGMP with a weight 3 units higher than wild type) with thefollowing final concentrations of cGMP in ng/mL: 1, 5, 10, 50, 100, 250,500, 1000, 2000.

TABLE 5 LC/MS conditions, Example 2C MS: Thermo Vantage Ion Mode: ESI⁺Scan Type: MRM Dwell Collision Retention Time Energy Time Compound:Transition (msec) (V) S Lens (min) cGMP 346 > 152 100 32 75 0.6 (+3)cGMP IS 349 > 155 100 32 75 0.6 HPLC: Waters Acquity UPLC Column: ThermoHypersil Gold 2.1 × 50 mm 1.9 micron particle size Flow Rate: 750 uL/minColumn RT Temperature: Autosampler 6° C. Temperature: Injection Volume:20 uL Mobile Phases: A = 100% Water + 0.1% Formic Acid B = 100%Acetonitrile + 0.1% Formic Acid Gradient: Time (min) % A % B 0 100 0 0.2100 0 0.3  50 50  0.7  50 50  0.8 100 0

Data were normalized to a high control using the following equation:100*(Sample−Low Control)/(High Control−Low Control), where the lowcontrol is the average of 16 samples treated with 1% DMSO, and the highcontrol is the average of 16 samples treated with 30 μM of I-329 Datawere fit using a 4-parameter fit (log(agonist) vs. response-variableslope) using GraphPad Prism Software v. 5. n=2 for all compounds. TheAbsolute EC₅₀ was interpolated from the curve fit and is defined as theconcentration at which a given compound elicits 50% of the high controlresponse. Compounds failing to elicit a minimum response of 50% arereported as >30 μM. For compounds run in duplicate or n higher than 2,the result herein given is the geometric mean of the several resultsobtained. Table 6 summarizes results obtained for selected compounds ofthe invention in this assay.

TABLE 6 Whole cell activity in the HEK assay with LC/MS detection(updated assay conditions, Example 2C). Absolute Absolute EC50 (uM) -EC50 (uM) - Compound binned (~) Compound binned (~) I-3 B I-200 C I-4 BI-204 B I-11 B I-206 A I-14 C I-213 A I-16 A I-214 A I-19 A I-219 A I-24A I-221 A I-35 B I-230 A I-39 B I-236 A I-41 A I-239 A I-53 B I-245 BI-54 A I-187 A I-55 B I-300 B I-59 B I-250 A I-67 C I-306 A I-69 B I-453B I-81 C I-361 A I-85 C I-257 C I-88 B I-258 B I-89 A I-454 A I-90 CI-363 C I-95 C I-364 A I-96 C I-365 B I-101 B I-366 A I-104 C I-455 AI-108 B I-367 A I-111 A I-368 C I-114 C I-369 A I-126 A I-370 A I-127 CI-268 A I-129 A I-371 A I-133 C I-269 C I-135 C I-372 B I-138 C I-329 AI-140 B I-330 A I-149 C I-373 B I-159 C I-374 A I-162 A I-375 C I-163 CI-307 B I-452 A I-305 A I-186 A I-376 C I-188 B I-339 A I-191 A I-377 AI-192 A I-308 B I-198 A I-312 B I-341 A I-348 C I-313 A I-321 A I-378 AI-432 A I-379 A I-433 C I-380 A I-350 A I-342 A I-434 A I-448 B I-334 BI-449 A I-335 B I-343 A I-336 C I-409 A I-435 A I-309 A I-407 A I-310 AI-437 B I-406 A I-410 C I-381 A I-337 A I-382 A I-408 A I-331 B I-395 AI-332 A I-411 B I-344 A I-322 A I-311 B I-351 A I-345 A I-352 A I-346 CI-413 C I-383 A I-438 A I-384 C I-323 B I-423 A I-353 C I-314 A I-439 AI-424 A I-324 B I-385 B I-396 A I-387 A I-397 A I-425 A I-398 C I-426 AI-399 A I-388 A I-354 A I-389 A I-440 B I-315 A I-355 A I-333 A I-358 AI-427 A I-441 B I-390 A I-451 B I-391 B I-400 B I-316 A I-325 A I-428 AI-442 C I-429 A I-443 B I-317 A I-326 B I-347 A I-414 C I-392 A I-360 AI-393 B I-356 B I-450 C I-401 C I-318 A I-416 C I-319 A I-412 C I-320 AI-357 C I-394 C I-164 B I-430 A I-405 B I-431 A I-327 C I-349 A I-328 CI-415 C I-499 C I-362 B I-500 B I-386 C I-501 C I-402 C I-502 B I-456 BI-503 B I-457 B I-504 C I-458 C I-505 B I-459 C I-506 C I-460 C I-507 CI-461 C I-418 B I-462 C I-508 A I-463 B I-509 A I-464 B I-446 C I-465 BI-445 B I-466 A I-510 B I-467 C I-511 C I-468 B I-419 C I-469 B I-512 CI-470 A I-513 C I-471 B I-514 A I-472 C I-515 A I-474 C I-516 C I-475 BI-517 C I-476 C I-518 A I-477 C I-519 B I-478 A I-520 B I-479 B I-521 AI-480 B I-522 A I-481 C I-523 C I-482 C I-524 C I-483 C I-525 C I-484 BI-526 C I-403 B I-527 B I-404 B I-528 C I-485 A I-529 C I-486 C I-530 BI-487 A I-531 A I-488 B I-532 C I-489 C I-420 A I-490 B I-533 B I-491 BI-534 C I-492 B I-535 B I-493 B I-536 A I-494 B I-537 A I-495 A I-538 AI-417 B I-539 C I-444 B I-540 B I-496 A I-541 C I-497 B I-542 B I-498 BI-543 B I-444 B I-544 A I-545 A I-547 B I-546 C I-548 C I-549 C I-600 BI-550 C I-601 C I-551 C I-602 C I-552 C I-603 B I-553 C I-604 B I-554 CI-605 B I-555 C I-606 B I-556 C I-607 B I-557 C I-608 A I-558 B I-609 CI-559 B I-610 B I-560 C I-611 B I-561 C I-612 A I-562 B I-613 B I-563 CI-614 B I-564 C I-615 C I-565 B I-616 B I-566 B I-617 C I-567 C I-618 CI-568 A I-619 C I-422 B I-620 C I-421 B I-621 C I-569 C I-622 A I-570 BI-623 C I-571 C I-624 B I-572 C I-625 C I-573 B I-626 C I-574 B I-627 BI-575 A I-628 C I-576 B I-629 C I-577 B I-630 C I-578 A I-634 A I-579 CI-631 A I-580 B I-632 C I-581 A I-633 A I-582 C I-591 B I-583 C I-592 CI-584 C I-593 C I-585 B I-594 C I-586 B I-595 B I-587 B I-596 C I-588 BI-597 C I-589 B I-598 C I-590 C I-599 C (~) Code definitions for the sGCenzyme activity values, expressed as Absolute EC₅₀ which is defined asthe concentration at which a given compound elicits 50% of the highcontrol response (I-329). Compounds failing to elicit a minimum responseof 50% are reported as >30 μM. EC50Abs < 100 nM = A; 101 nM ≤ EC50Abs <1000 nM = B; 1001 nM ≤ EC50Abs = C.

Example 3A: Biological Activity Measurement by the Thoracic Aortic RingsAssay

Thoracic aortic rings are dissected from anesthetized (isoflurane) maleSprague-Dawley rats weighing 275-299 g. Tissues are immediatelytransferred to ice-cold Krebs-Henseleit solution, which has been aeratedwith 95% O₂ and 5% CO₂ for 30 minutes. Following removal of connectivetissue, aortic sections are cut into 4 rings (˜2 mm each) and suspendedon 2 L-shaped hooks, with one hook fixed at the bottom of the tissuebath (Schuler Organ Bath, Harvard Apparatus) and the other connected toa force transducer (F30 Force Transducer, Harvard Apparatus). Bathscontaining Krebs Henseleit solution (10 mL) are heated to 37° C. andaerated with 95% O₂ and 5% CO₂. Rings are brought to an initial tensionof 0.3-0.5 g and gradually raised to a resting tension of 1.0 g over 60minutes. Rings are rinsed with Krebs Henseleit solution (heated to 37°C. and aerated with 95% O₂ and 5% CO₂) at 15 minute intervals until astable baseline is obtained. Rings are considered to be stable after aresting tension of 1.0 g is maintained (for approximately 10 minutes)without need for adjustment. Rings are then contracted with 100 ng/mLphenylephrine by adding 100 uL of a 10 g/mL phenylephrine stocksolution. Tissues achieving a stable contraction are then treated in acumulative, dose dependent manner with test compounds prepared indimethylsulfoxide (DMSO). In some cases, tissues are rinsed three timesover a 5 minute period with Krebs-Heinseleit's solution (heated to 37°C. and aerated with 95% O₂ and 5% CO₂), allowed to stabilize atbaseline, and then used for characterization of other test articles orDMSO effects. All data are collected using the HSE-ACAD softwareprovided by Harvard Apparatus. Percent relaxation effects are calculatedin Microsoft Excel using the recorded tension value of 100 ng/mLphenylephrine treatment as 0% inhibition and treatment with 100 μM3-isobutyl-1-methylxanthine as 100% inhibition. EC₅₀ values arecalculated from concentration-response curves generated with GraphPadPrism Software.

Example 3B: Biological Activity Measurement by the Thoracic Aortic RingsAssay, Alternative Method

As an alternative thoracic aortic rings assay, the procedure of Example3 is used except that percent relaxation effects are calculated inMicrosoft Excel using the recorded tension value of 100 ng/mLphenylephrine treatment as 0% inhibition and, after washing the tissuewith buffer, the original resting tension of the tissue is used as 100%inhibition.

Example 4: Blood Pressure Change in Sprague-Dawley Rats

Male rats (250-350 g body weight, supplied by Harlan Laboratories) wereanesthetized with ketamine/xylazine and a heparinized saline fluidfilled catheter implanted into the right femoral artery. The catheterwas exteriorized between the scapula, capped, and the animal allowed torecover for at least 7 days post surgery prior to any compound testing.Prior to testing animals were maintained on normal diet, with freeaccess to drinking water, under a 12 hour light-dark cycle.

On the day of experimentation, under inhaled isoflurane anesthesia, thecatheter was uncapped and connected to a tether (Instech Labs) andpressure transducer (Harvard Apparatus). Blood pressure and heart ratewere subsequently captured and analyzed with a dedicated data capturesystem (PowerLab, ADInstruments). Data sampling rates were set at 1cycle per second. Once connected, each rat was allowed to recover fromanesthesia and baseline blood pressure and heart rate levels wereestablished in these conscious, freely-moving animals. Once baseline wasestablished either vehicle (0.5% methylcellulose or 100% PEG400) or testarticle was administered orally (PO, 10 mg/kg) and the effects on bloodpressure and heart rate monitored for up to 24 hours.

Data are reported as hourly averages and changes in blood pressure arecalculated from subtracting individual baseline on an hourly basis.

Rat Mean Arterial Pressure Compound peak change from Number baseline at10 mpk@ I-89 C I-121 A I-124 B I-142 A I-143 B I-161 B I-185 A I-186 BI-248 C I-253 B I-306 B I-313 C I-315 C I-316 C I-324 C I-187 A I-329 BI-330 C I-337 C I-341 A I-342 C I-388 B I-389 C I-400 B I-405 C @Codedefinitions for Rat Mean Arterial Pressure peak change from baseline at10 mpk: A = −10 < peak change from baseline at 10 mpk < 0 B = −20 ≤ peakchange from baseline at 10 mpk ≤ −10 C = peak change from baseline at 10mpk < −20

Example 5: Animal Models Descriptions Lamb Model of PulmonaryHemodynamics Using Inhaled sGC Stimulator

(“Inhaled Agonists of Soluble Guanylate Cyclase Induce SelectivePulmonary Vasodilation”, Oleg V. et al, American J of Resp and CriticalCare Medicine, Vol 176, 2007, p 1138)

It is possible to test whether inhalation of novel dry-powdermicroparticle formulations containing sGC stimulators would produceselective pulmonary vasodilation in lambs with acute pulmonaryhypertension by following a published procedure. It is also possible toevaluate the combined administration of the microparticles of sGCstimulator and inhaled nitric oxide (iNO) in this system. Finally, it ispossible to examine whether inhaling microparticles of an sGC stimulatorwould produce pulmonary vasodilation when the response to iNO (induciblenitric oxide synthase) is impaired.

Protocol: In awake, spontaneously breathing lambs instrumented withvascular catheters and a tracheostomy tube, U-46619 is infusedintravenously to increase mean pulmonary arterial pressure to 35 mm Hg.Inhalation of microparticles composed of either BAY 41-2272, BAY41-8543, or BAY 58-2667 and excipients (dipalmitoylphosphatidylcholine,albumin, lactose) produced dose dependent pulmonary vasodilation andincreased transpulmonary cGMP release without significant effect on meanarterial pressure. Inhalation of microparticles containing BAY 41-8543or BAY 58-2667 increased systemic arterial oxygenation. The magnitudeand duration of pulmonary vasodilation induced by iNO were augmentedafter inhaling BAY 41-8543 microparticles. Intravenous administration of1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), which oxidizes theprosthetic heme group of sGC, markedly reduced the pulmonary vasodilatoreffect of iNO. In contrast, pulmonary vasodilation and transpulmonarycGMP release induced by inhaling BAY 58-2667 microparticles were greatlyenhanced after treatment with ODQ. Thus, inhalation of microparticlescontaining agonists of sGC may provide an effective novel treatment forpatients with pulmonary hypertension, particularly when responsivenessto iNO is impaired by oxidation of sGC. Note: BAY 41-2272, BAY 41-8543are sGC stimulators whereas BAY 58-2667 is an sGC activator.

Electrical Field Stimulated Guinea Pig Tracheal Smooth Muscle In Vitro(Ex Vivo) Model for the Assessment of Bronchodilation.

It is possible to assess the bronchodilating effects of sGC stimulatorsby using the system described below. This system allows us to determinepotency, efficacy and duration of action of several sGC stimulators, aswell as to assess potential side effects such as blood pressure, orheart rate changes.

Animals: Guinea pig, Dunkin Hartley, male, Full barrier-bred andcertified free of specific micro-organisms on receipt 525-609 g on theexperimental day, Harlan UK Ltd. Guinea pigs are housed in a group of 4in solid-bottomed cages with Gold Flake bedding in a controlledenvironment (airflow, temperature and humidity). Food (FD1, Special DietServices) and water are provided ad libitum.

Guinea Pig Tracheal Smooth Muscle Contraction in Response to EFS.Assessment of Compound Potency and Efficacy:

On each experimental day, a guinea pig is killed by exposure to a risingconcentration of CO₂ and the trachea removed. The trachea is cleaned ofextraneous tissue and cut open longitudinally in a line opposite themuscle, opened out and cut into strips 2-3 cartilage rings wide. Acotton loop is attached to one end of each tracheal strip and a lengthof cotton to the other end. Tracheal strips are then suspended betweentwo platinum electrodes, using tissue holders, in a Myobath system(World Precision Instruments Stevenage, UK). The loop is attached overthe hook at the bottom of the tissue holder and the other end attachedto the arm of a FORT10 force transducer (World Precision InstrumentsStevenage, UK) ensuring that the tissue is positioned between the twoplatinum electrodes. The whole assembly is then lowered into a 10 mltissue bath containing modified Kreb's-Henseleit buffer, at 37° C.,bubbled with Carbogen. A 1 g tension is applied to each piece of tissueand the tissue washed, followed by a 1 hour stabilization period. Oncethe tissues has been allowed to stabilize, the apparatus for electricalfield stimulation is set to deliver a stimulation of frequency 80 Hzpulse width 0.1 ms, with a gated, uni-polar pulse, every 2 minutes usinga DS8000 8 channel digital stimulator (World Precision InstrumentsStevenage, UK). A voltage response curve is carried out on each trachealstrip at 2, 4, 6, 7, 8, 10, 12 V and a sub-maximal voltage then selectedto apply to each tissue during the remainder of the experiment. Guineapig tracheal smooth muscle (GPTSM) contraction is induced usingsub-maximal Electrical Field Stimulation (EFS) (It is also possible toinduce contraction by using a spasmogen substance, such as methacholineor histamine as described in Coleman et al.*). Compounds are dissolvedin 100% DMSO at 3×10-2M and aliquots stored at −200 C. A separatealiquot is used for each experiment. Tissues are washed with Kreb'sbuffer and stimulated using the previously determined sub-maximalvoltage for 1 hour to establish a stable baseline contraction prior toassessment of compound activity.

A cumulative dose response curve (DRC) to each test substance is thenperformed and changes in smooth muscle contraction measured. The effectof each test substance in each experiment is expressed as a percentageinhibition of the baseline contraction, normalized to the relevantvehicle controls. The experiment is performed three times, using tissuefrom three different animals. The data from all three experiments arepooled, the DRC plotted, and the test substance potency and efficacydetermined. The potency of Ipratropium bromide is assessed alongside thetest compounds and the IC50 determined to be 0.86 nM (95% Cl,0.78-0.94), in agreement with data previously produced in the system.

Novel and Versatile Superfusion System. Its use in the Evaluation ofSome Spasmogenic and Spasmolytic Agents Using Guinea pig isolatedTracheal Smooth Muscle.”, R. A. Coleman et al., J. Pharmacol. Methods,21, 71-86, 1989.Mouse Model for Diseases in which Altered CFTR-Function is CausallyInvolved

These diseases comprise cystic fibrosis, pancreatic disorders,gastrointestinal disorders, liver disorders, cystic fibrosis-relateddiabetes (CFRO), dry eye, dry mouth and Sjoegren's syndrome.

By using transgenic mice expressing or not expressing the delta F508CFTRchannel it is possible to measure differences on nasal potentialdifference and salivation in the presence of a test sGC stimulator byusing the literature protocol described below (see WO2011095534).

Salivary Secretion Assay in Delta(0.6.)50S-CFTR Mice

15 Male and female homozygous, heterozygous 0.6.505-CFTR (backcrossed onthe FVB genetic background for more than 12 generations, originallyobtained from Erasmus University, Rotterdam; 10-14 weeks old andweighing 1S-36 g of both sexes were used in this assay. Solutions ofVardenafil in concentrations of 0.07, 0.14 and 0.42 mg/kg BW were 20prepared in sterile saline, whereas the sGC stimulator BAY 41-2272 wasdissolved to 0.01, 0.03, 0.1 and 0.3 mg/kg BW in a solvent containing50% ddH20, 40% PEG 400 (polyethylene glycol 400) and 10% ethanol. Thesubstances or the appropriate vehicles were administered to mice viaintraperitoneal injection (5 ml/kg BW) 60 min prior to the salivarysecretion assay. After 60 min, mice were anaesthetized with acombination of 25 ketamine and diazepam. The solution was prepared tocontain 1 ml of 5 mg/ml diazepam. and 1 ml of 100 mg/ml ketamine in 8 mlsterile saline. Anaesthesia was induced by intraperitoneal injection ofthe solution (10 ml/kg BW). After anaesthesia, mice were pretreated witha subcutaneous injection of 1 mM atropine (50 1-11) into the left cheekin order to avoid a cross-stimulation of cholinergic receptors. Smallstrips of Whatman filter 5 paper were placed inside the previouslyinjected cheek for 4 min to absorb any saliva secreted after theinjection of atropine. This first piece of filter paper was removed andreplaced with a second pre-weighed filter paper. Thereafter, 50 1-11 ofa solution containing 100 I-IM isoprenaline and 1 mM atropine wasinjected into the left cheek at the same site to induce the salivarysecretion by adrenergic mechanisms. The time of the 10 isoprenalineinjection was taken as time zero, and filter paper stripes were replacedevery 10 minutes for a total collection period of 30 minutes. Each pieceof filter paper was immediately placed and sealed in a pre-weighed vial.After all samples had been collected, each vial was re-measured and theweights of all samples were recorded. The difference in total weight ofvial plus paper measured before and after collecting saliva 15 was takenas the net weight of saliva secreted during the collection period. Thetotal amounts of salivary secretion were calculated as the weight ofsaliva divided by the number of minutes required for each collection andthen normalized to the mass of the mouse in grams. Results are expressedas the mean percentage increase of n mice compared to placebo treatment.Statistics was analyzed by one way ANOVA test 20 followed by post-hocBonferoni analysis; */**/*** means statistical significant with pvalues<0.05/<0.01/0.001 and n.s. means non significant.

These animal studies were carried out with a number of sGC stimulators,sGC activators and PDE5 inhibitors. The results suggests that compoundsof the invention are useful for the treatment of cystic fibrosis,pancreatic disorders, gastrointestinal disorders, liver disorders,Cystic Fibrosis-related diabetes (CFRO), dry eye, dry mouth andSjoegren's syndrome.

Neuromuscular Disorders

It has previously been shown that neuronal Nitric Oxide Synthase (nNOS)mislocalization from the sarcolemmal membrane to the sarcoplasm isobserved in a broad range of nondystrophic neuromuscular conditionsassociated with impaired motility status and catabolic stress. One toolfor the evaluation of muscle biopsies of patients with a variety ofinherited and acquired forms of neuromuscular disorders is theassessment of sarcolemal localization of nNOS. It was found that thelevel of nNOS at the sarcolemma correlates with mobility and functionalstatus.

An analogous assessment can be used to determine nNOS localization inanimal models of nondystrophic myopathy following the literatureprotocols described below (“Loss of sarcolemmal nNOS is common inacquired and inherited neuromuscular disorders”; E. L. FinangerHedderick et al., Neurology, 2011, 76(11), 960-967).

nNOS Mislocalization in Mouse Models of Acquired Muscle Atrophy

Two mouse models have been described that demonstrate muscle atrophywithout compromised mobility: high-dose corticosteroids therapy andshort-term starvation. Mice treated with steroids or starved for 48hours showed significant decreases in overall body mass and innormalized wet skeletal muscle mass. Morphometric analysis of skeletalmuscle specimens of both models demonstrated muscle atrophy, as definedby a significant decrease in mean minimal Feret fiber diameter ascompared to age-matched controls (n=5 for each group).Immunofluorescence staining for dystrophin, α-sarcoglycan, andα-1-syntrophin showed normal dystrophin localization suggestive of anintact DGC complex However, both steroid-treated and starved mice showedabsent or severely reduced sarcolemmal nNOS staining. Real-time PCR forNOS family proteins (nNOS, eNOS, iNOS) revealed no significantdifferences in expression levels of any of the 3 transcripts insteroid-treated mice (n=8 for each group). Moreover, Western blotanalysis for nNOS, iNOS, and eNOS showed no differences in proteinlevels.

These murine animal models could be used to assess the effects of sGCstimulators (for example an sGC stimulator of the invention) in thesymptoms of muscle atrophy and related disease states.

Starved mice exhibited a 1-fold decrease of nNOS and iNOS transcriptexpression as compared to wildtype mice (n=9 for controls, n=7 forstarved). However, the protein level of nNOS, iNOS, and eNOS revealed nodifferences between control and starved mice (n=4 for each group). Thesedata demonstrate that abnormal localization of nNOS occurs in mice withsevere muscle atrophy even if overall mobility is preserved, supportingthe notion that, in addition to impaired mobility, other triggers suchas catabolic stress may be associated with sarcolemmal loss of nNOS.

Skeletal Muscle nNOS Localization is Maintained During Hibernation(Studies with Squirrels)

Skeletal muscle specimens from hibernating 13-lined ground squirrelshave been used to evaluate the impact of immobility and catabolic stresson nNOS localization in the context of maintained muscle homeostasis andintegrity. These animals are obligate hibernating mammals that areprotected against skeletal muscle atrophy during hibernation. Despitehibernating for 5 months with almost complete immobility and no caloricintake, sarcolemmal expression of nNOS is preserved. These data togetherwith patient and mouse data indicate that biochemical control of nNOSlocalization is complex and, importantly, that preserved sarcolemmalnNOS may be significant in maintaining muscle homeostasis.

These results also suggest that targeting aberrant NO signaling (forinstance with sGC stimulators such as the ones here described) may provebeneficial for a broad group of patients with neuromuscular disorders.

Mouse Models of Muscular Dystrophy (BMD and DMD)

Becker muscular dystrophy (BMD), characterized by progressive skeletalmuscle wasting, is caused by mutations of the muscle protein dystrophin.In a human study, Martin et al. (see “Tadalafil Alleviates MuscleIschemia in Patients with Becker Muscular Dystrophy”; Elizabeth A.Martin et al., Sci. Transl. Med. 4, 162ra155 (2012); “Vascular-targetedtherapies for Duchenne muscular dystrophy”; Ennen et al., SkeletalMuscle, 2013, 3:9) assessed exercise-induced attenuation of reflexsympathetic vasoconstriction in the muscles of 10 patients with BMD and7-age matched healthy male controls. This is a protective mechanism thatoptimizes perfusion of skeletal muscle to meet the metabolic demands ofexercise. Reflex vasoconstriction was induced by simulated orthostaticstress and was measured as the forearm muscles were rested or lightlyexercised in the form of rhythmic handgrip. First, the investigatorsshowed that exercise-induced attenuation of reflex vasoconstriction wasdefective in 9 out of 10 patients with BMD in whom the common dystrophinmutations disrupt targeting of neuronal NO synthase (nNOS) to the musclesarcolemma. Then, in a double-blind randomized placebo-controlledcrossover trial, the authors showed that normal blood flow regulationwas restored in eight of nine patients by a single oral dose of 20 mg oftadalafil, a specific PDE5 inhibitor.

It is possible to assess the effects of drugs acting on the NO pathwayby using a dystrophin-deficient mdx mouse model of related diseaseDuchene muscular dystrophy (DMD). This model has also shown thatinhibitors of phosphodiesterase 5 (PDE5) alleviate some features of thedystrophic phenotype including vasospasm of skeletal muscle microvesselsthat can lead to muscle injury and fatigue.

With exercise of healthy skeletal muscle, sarcolemmal nNOS derived NOattenuates local α-adrenergic vasoconstriction, thereby optimizingperfusion to meet the metabolic demands of the active muscle. Thisprotective mechanism (termed functional sympatholysis) is lost in mdxmice (a model of BMD and DMD), nNOS null mice, and boys with DMD causingfunctional muscle ischemia. Repeated bouts of functional ischemia couldaccelerate use-dependent injury of muscle fibers already weakened bydystrophin deficiency.

In the mdx mouse, many features of the dystrophic phenotype can beimproved by multiple strategies that boost NO signaling, includingtransgenic expression of nNOS, transgenic expression of dystrophinminigenes that restore sarcolemmal nNOS (and thereby restore functionalsympatholysis), administration of the NOS substrate L-arginine (24, 25),treatment with NO-donating drugs, and phosphodiesterase 5A (PDE5A)inhibition with the drug tadalafil or sildenafil. These PDE5Ainhibitors, which prolong the halflife of guanosine 3′,5′-monophosphate(cGMP)—the downstream target of NO in vascular smooth muscle-were shownin the mdx mouse to alleviate muscle ischemia, as well as injury andfatigue, after a brief bout of exercise. Also, these drugs were shown toimprove cardiac dynamics in mdx mice and to rescue dystrophic skeletalmuscle and prolong survival in dystrophin-deficient zebrafish.

These findings support an essential role for sarcolemmal nNOS inmodulating sympathetic vasoconstriction in exercising human skeletalmuscles and suggests that targeting the aberrant NO pathway (forinstance by using an sGC stimulator of the invention) may be a usefultherapeutic approach for treating BMD and DMD in humans.

Sickle Cell Disease

Sickle-cell disease (SCD), or sickle-cell anaemia (SCA) ordrepanocytosis, is a hereditary blood disorder, characterized by redblood cells that assume an abnormal, rigid, sickle shape. Sicklingdecreases the cells' flexibility and results in a risk of variouscomplications. The sickling occurs because of a mutation in thehaemoglobin gene. Individuals with one copy of the defunct gene displayboth normal and abnormal haemoglobin. This is an example of codominance.In 1994, in the US, the average life expectancy of persons with thiscondition was estimated to be 42 years in males and 48 years in females,but today, thanks to better management of the disease, patients can liveinto their 70s or beyond.

Sickle-cell anaemia is a form of sickle-cell disease in which there ishomozygosity for the mutation that causes HbS. Sickle-cell anaemia isalso referred to as “HbSS”, “SS disease”, “haemoglobin S” orpermutations of those names. In heterozygous people, that is, those whohave only one sickle gene and one normal adult haemoglobin gene, thecondition is referred to as “HbAS” or “sickle cell trait”. Other, rarerforms of sickle-cell disease are compound heterozygous states in whichthe person has only one copy of the mutation that causes HbS and onecopy of another abnormal haemoglobin allele. They includesickle-haemoglobin C disease (HbSC), sickle beta-plus-thalassaemia(HbS/β⁺) and sickle beta-zero-thalassaemia (HbS/β⁰).

Although red blood cell (RBC) sickling and rheologic abnormalities arecentral to the pathophysiology of sickle cell disease, vasculardysfunction resulting from complex interactions between sickled redblood cells (sRBC), endothelial cells, platelets and leukocytes play anequally important role. In sickle cell disease, endothelial activationis associated with sickle cell-mediated hypoxia-reperfusion events (seefor example “Advances in understanding of the pathogenesis ofcerebrovascular vasculopathy in sickle cell anemia”, P. Connes et al.,Br. J. Haematol. 2013, 161, 484-98). Red blood cell sickling andadhesion to endothelium initiate vaso-occlusion by impairing blood flow.The subsequent surge of inflammatory mediators and endothelialactivation trigger a cascade of events leading to vascular damage.Pathophysiological responses to intermittent hypoxia-reperfusion fromthese vaso-occlusive events are demonstrated by an increased productionof cytokines, leukocyte up-regulation and activation of pro-coagulantand adhesion molecules, with simultaneous inhibition of cytoprotectivemediators.

Leukocytosis is correlated with nearly every manifestation of sicklecell disease, emphasizing the influential role of inflammation in thepathophysiology of sickle vasculopathy. Even at baseline, sickle celldisease patients exhibit elevations in pro-inflammatory cytokines,including C-reactive protein (CRP), tumor necrosis factor (TNF),interleukin-1 (IL-1) and interleukin-8 (IL-8). In vitro studies haveshown that sRBC promote endothelial up-regulation of TNF-α and IL-1-β(8-10). Microarray studies of activated monocytes have showndifferential expression of genes involved in inflammation, hememetabolism, cell cycle regulation, anti-oxidant responses, andangiogenesis. More recently, it was shown that differential expressionof nuclear factor κ-light-chain-enhancer of activated B cells(NFκB/p65), Kruppel-like factor 2 (KLF2), and other transcriptionfactors that regulate pathways of inflammation in sickle cell diseasechildren at increased risk for stroke.

In transgenic mouse models (see “Novel Therapies Targeting theEndothelium in sickle cell disaease”, C. C Hoppe, Hemoglobin, 35(5-6):530-546 (2011) and references cited therein), sickling inducingoxidative stress has been shown to affect microvascular regulatorymechanisms leading to endothelial activation and exaggeratedinflammatory and pro-adhesive responses. Oxidative stress occurs throughformation of reactive oxygen species (ROS). Depletion of NO occursthrough hemoglobin (Hb) mediated scavenging, consumption by ROS andarginase-mediated substrate depletion. In sickle cell disease, thescavenger systems that normally remove circulating free Hb aresaturated. Free Hb depletes NO, leading to endothelial dysfunction.Consequently, the normal balance of vasoconstriction and vasodilation isskewed towards vasoconstriction, endothelial activation, oxidativestress and proliferative vasculopathy.

Therapies directed at restoring NO homeostasis have shown promise inpreliminary studies in patients with sickle cell disease. Previous invitro studies and studies in other patient populations showedNO-mediated down-regulation of endothelial adhesion molecule expression.Following these observations, the use of inhaled NO was studied insickle cell disease children presenting with VOE and found associatedtrends toward lower pain scores, decreased analgesic requirements and ashorter hospital stay.

These findings were reproduced in a recent randomized placebo controlledtrial evaluating inhaled NO for the treatment of acute VOE in adultpatients with sickle cell disease, showing that inhaled NO significantlyreduced pain scores and was associated with a trend towards decreaseduse of parenteral morphine compared with placebos. Results from acompleted phase II trial of adult sickle cell disease patients treatedwith inhaled NO for acute VOE have not yet been made available(clinicaltrials. gov NCT00023296). Another phase II trial of inhaled NOfor VOE treatment in children with sickle cell disease is expected to becompleted (clinicaltrials.gov NCT00094887). The possible therapeuticrole of inhaled NO for ACS in sickle cell disease is currently beingassessed in both children and adults in two separate French phase II/IIItrials comparing the use of inhaled NO to placebo or standard care inchildren with ACS (clinicaltrials.gov NCT01089439 and NCT00748423).

Dietary supplementation of the NO synthase substrate, L-arginine, hasbeen studied extensively in sickle cell disease as a means of increaseNO bioavailability. In sickle mice, oral L-arginine at high doses hasbeen shown to decrease Gardos channel activity, dense cell formation andhemolysis, as well as functional improvements in vascular reactivity.

Sildenafil, an agent aimed at amplifying the effect of endogenous NO byinhibiting PDE5, a downstream mediator of NO, is used widely in thegeneral population to treat primary PHT. Preliminary studies in sicklecell disease patients with severe PHIT reported improvements in PAP andexercise capacity after treatment with sildenafil. A multicenter trial(Treatment of Pulmonary Hypertension and Sickle Cell Disease withSildenafil Therapy, Walk-PHaSST) testing the safety and efficacy ofsildenafil in sickle cell disease patients with Doppler-defined PHT wasstopped prematurely due to a higher frequency of serious side effects,including increased rates of VOE, headache, and visual disturbance inthe treatment group.

Nitrite and niacin have also been investigated for their direct NO donorproperties. In a pilot phase I/II clinical trial, sodium nitriteinfusions in adult sickle cell disease patients enhanced forearm bloodflow, consistent with a NO donor mechanism of action. A larger phaseI/II trial is now investigating whether nitrite infusions administeredas adjunctive therapy during acute VOE will improve microvascular bloodflow and tissue oxygenation (clinicaltrials.gov NCT01033227). The effectof niacin on improvement in endothelial-dependent vasodilation is alsobeing assessed in a phase II randomized, controlled trial(clinicaltrials.gov NCT 00508989).

The above results suggest that targeting the aberrant NO pathway insickle cell disease (for instance by using an sGC stimulator of theinvention) may be a useful therapy for the treatment of the disease.Murine models of sickle cell anemia that could be used to assess theeffect of sGC stimulators (e.g., an sGC stimulator of the invention) inthis disease state, are described in Blood, 2001, 98(5), 1577-84; J.Clin. Invest. 2004, 114(8), 1136-45; and Br. J Haematol, 2004, 124(3),391-402.

Bladder Dysfunction

It has been shown that the sGC activator BAY 60-2770 amelioratesoveractive bladder in obese mice (see “The Soluble Guanylyl CyclaseActivator BAY 60-2770 ameliorates overactive bladder in obese mice”,Luiz O Leiria et al., The Journal of Urology, 2013,doi:10.1016/j.juro.2013.09.020). The animal model described in thispublication can analogously be used to assess the effect of an sGCstimulator (for example, an sGC stimulator of the invention) onoveractive bladder.

The same group of researchers have also described a rat model of bladderdysfunction (NO-deficient rats, F Z Monica et al., Neurology andUrodynamics, 30, 456-60, 2011) and have shown the protective effects ofBAY-2272 (an sGC activator) in this model. The animal model described inthis publication can analogously be used to assess the effect of an sGCstimulator (for example, an sGC stimulator of the invention) on bladderdysfunction related to detrusor smooth muscle overactivity.

A number of embodiments have been described. Nevertheless, it will beunderstood that various modifications may be made without departing fromthe spirit and scope of the invention.

1-140. (canceled)
 141. A compound represented by Formula XIa or FormulaXIb:

wherein J^(B) is halogen; R¹ is hydrogen or C₁₋₆ alkyl; R² is a C₁₋₆alkyl group optionally and independently substituted by up to threeinstances of R^(5a); each R^(5a) is independently selected from halogen,—CN, C₁₋₆ alkyl, —(C₁₋₆ alkyl)R^(6a), —OR^(6a), —SR^(6a), —COR^(6a),—OC(O)R^(6a), —C(O)OR^(6a), —C(O)N(R^(6a))SO₂R^(6a),—N(R^(6a))C(O)R^(6a), —N(R^(6a))C(O)OR^(6a), —N(R^(6a))C(O)N(R^(6a))₂,—N(R^(6a))₂, —SO₂R^(6a), —SO₂OH, —SO₂NHOH, —SO₂N(R^(6a))₂,—SO₂N(R^(6a))COOR^(6a), —SO₂N(R^(6a))C(O)R^(6a), —N(R^(6a))SO₂R^(6a),—(C═O)NHOR^(6a), a C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclicring, a 5 or 6-membered heteroaryl ring, phenyl, benzyl, an oxo group ora bicyclic group: wherein each 5 or 6-membered heteroaryl ring or 4 to7-membered heterocyclic ring contains up to 4 ring heteroatomsindependently selected from N, O and S, wherein each of said C₁₋₆ alkyl,C₁₋₆ alkyl portion of the —(C₁₋₆ alkyl)R^(6a) moiety, C₃₋₈ cycloalkylring, 4 to 7-membered heterocyclic ring, 5 or 6-membered heteroarylring, benzyl or phenyl group is optionally and independently substitutedwith up to 3 instances of halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —OH,—NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —CONH₂, —COO(C₁₋₄alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo; wherein said bicyclicgroup contains ring one and ring two in a fused or bridged relationship,said ring one is a 4 to 7-membered heterocyclic ring, a 5 or 6-memberedheteroaryl ring, phenyl or benzyl, and said ring two is a phenyl ring ora 5 or 6-membered heteroaryl ring containing up to 3 ring heteroatomsselected from N, O or S; and wherein said bicyclic group is optionallyand independently substituted by up to six instances of halogen, C₁₋₄alkyl, —OH, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —CONH₂,—COO(C₁₋₄ alkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo; and eachR^(6a) is independently selected from hydrogen, a C₁₋₆ alkyl, phenyl,benzyl, a C₃₋₈ cycloalkyl ring, a 4 to 7-membered heterocyclic ring or a5 or 6-membered heteroaryl ring, wherein each of said C₁₋₆ alkyl, eachof said phenyl, each of said benzyl, each of said C₃₋₈ cycloalkyl group,each of said 4 to 7-membered heterocyclic ring and each of said 5 or6-membered heteroaryl ring is optionally and independently substitutedwith up to 3 instances of halogen, C₁₋₄ alkyl, —OH, —NH₂, —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)₂, —CN, —COOH, —C(O)NH₂, —C(O)N(C₁₋₆ alkyl)₂,—C(O)NH(C₁₋₆ alkyl), —C(O)N(C₁₋₆ haloalkyl)₂, —C(O)NH(C₁₋₆ haloalkyl),C(O)N(C₁₋₆ alkyl)(C₁₋₆ haloalkyl), —COO(C₁₋₆ alkyl), —COO(C₁₋₆haloalkyl), —O(C₁₋₄ alkyl), —O(C₁₋₄ haloalkyl) or oxo, wherein each ofsaid 5 or 6-membered heteroaryl ring or 4 to 7-membered heterocyclicring contains up to 4 ring heteroatoms independently selected from N, Oand S.
 142. The compound of claim 141, or a pharmaceutically acceptablesalt thereof, wherein R² is a C₁₋₃ alkyl group optionally andindependently substituted by up to three instances of R^(5a); whereineach instance of R^(5a) is independently selected from hydroxyl and C₁₋₂haloalkyl.
 143. (canceled)
 144. A pharmaceutical composition comprisinga compound of claim 141, or a pharmaceutically acceptable salt thereof,and one or more excipients.
 145. A method of treating a disease, healthcondition or disorder in a subject in need of treatment, comprisingadministering a therapeutically effective amount of the compound ofclaim 141, or a pharmaceutically acceptable salt thereof, to the subjectin need of treatment, wherein the disease, health condition or disorderis selected from: (1) a peripheral, pulmonary, hepatic, kidney, cardiacor cerebral vascular/endothelial disorders/conditions or diseasesotherwise related to circulation selected from: disorders related tohigh blood pressure and decreased coronary blood flow; increased acuteand chronic coronary blood pressure; arterial hypertension; vasculardisorder resulting from cardiac and renal complications, heart disease,stroke, cerebral ischemia or renal failure; resistant hypertension;diabetic hypertension; congestive heart failure; diastolic or systolicdysfunction; coronary insufficiency; arrhythmias; reduction ofventricular preload; cardiac hypertrophy; heart failure/cardiorenalsyndrome; portal hypertension; endothelial dysfunction or injury;thromboembolic disorders and ischemias; myocardial infarction; stroke;transient ischemic attacks (TIAs); obstructive thromboanginitis; stableor unstable angina pectoris; coronary spasms; variant angina;Prinzmetal's angina; restenosis resulting from thrombolysis therapies;thrombogenic disorders; Alzheimer's disease; Parkinson's disease;dementia; vascular cognitive impairment; cerebral vasospasm; traumaticbrain injury; peripheral arterial disease; peripheral occlusive arterialdisease; peripheral vascular disease; hypertonias; Raynaud's syndrome orphenomenon; critical limb ischemia; vasculitis; peripheral embolism;intermittent claudication; vaso-occlusive crisis; Duchene's musculardystrophy; Becker muscular dystrophy; microcirculation abnormalities;vascular leakage or permeability issues; shock; sepsis; cardiogenicshock; control of leukocyte activation; inhibition or modulation ofplatelet aggregation; pulmonary/respiratory conditions; pulmonaryhypertension; pulmonary arterial hypertension and associated pulmonaryvascular remodeling; localized thrombosis and right heart hypertrophy;pulmonary hypertonia; primary pulmonary hypertension; secondarypulmonary hypertension; familial pulmonary hypertension; sporadicpulmonary hypertension, pre-capillary pulmonary hypertension; idiopathicpulmonary hypertension; thrombotic pulmonary arteriopathy; plexogenicpulmonary arteriopathy; cystic fibrosis; bronchoconstriction orpulmonary bronchoconstriction; acute respiratory distress syndrome; lungfibrosis; lung transplant; pulmonary hypertension associated with orrelated to left ventricular dysfunction, hypoxemia, WHO groups I, II,III, IV and V hypertensions, mitral valve disease, constrictivepericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis,pulmonary fibrosis, anomalous pulmonary venous drainage, pulmonaryvenooclusive disease, pulmonary vasculitis, collagen vascular disease,congenital heart disease, pulmonary venous hypertension, interstitiallung disease, sleep-disordered breathing, sleep apnea, alveolarhypoventilation disorders, chronic exposure to high altitude, neonatallung disease, alveolar-capillary dysplasia, sickle cell disease;coagulation disorders; chronic thromboembolism, pulmonary embolism dueto tumor, parasites or foreign material, connective tissue disease,lupus, schistosomiasis, sarcoidosis, chronic obstructive pulmonarydisease, asthma, emphysema, chronic bronchitis, pulmonary capillaryhemangiomatosis; histiocytosis X, lymphangiomatosis and compressedpulmonary vessels due to adenopathy, tumor or fibrosing mediastinitis;arterosclerotic diseases or conditions; atherosclerosis; atherosclerosisassociated with endothelial injury, platelet and monocyte adhesion andaggregation, smooth muscle proliferation and migration; restenosis;restenosis developed after thrombolysis therapies, percutaneoustransluminal angioplasties (PTAs), percutaneous transluminal coronaryangioplasties (PTCAs) and bypass; inflammation; cardiovascular diseaseassociated with metabolic syndrome, obesity, dyslipidemia, diabetes,high blood pressure; lipid related disorders such as dyslipidemia,hypercholesterolemia, hypertriglyceridemia, sitosterolemia, fatty liverdisease, and hepatitis; preeclamsia; polycystic kidney diseaseprogression; subcutaneous fat accumulation; liver cirrhosis; livercirrhosis associated with chronic liver disease; hepatic fibrosis,hepatic stellate cell activation, hepatic fibrous collagen; totalcollagen accumulation; liver disease of necro-inflammatory and/or ofimmunological origin; urogenital system disorders; renal fibrosis; renalfailure resulting from chronic kidney diseases or insufficiency; renalfailure due to accumulation/deposition and tissue injury, progressivesclerosis and glomerulonephritis; prostatic hypertrophy; systemicsclerosis; cardiac interstitial fibrosis; cardiac remodeling andfibrosis; cardiac hypertrophy; (2) ischemia, reperfussion damage;ischemia/reperfussion associated with organ transplant, lung transplant,pulmonary transplant or cardiac transplant; conserving bloodsubstituents in trauma patients; (3) a sexual, gynecologicalandurological disorders selected from erectile dysfunction; impotence;premature ejaculation; female sexual dysfunction; female sexual arousaldysfunction; hypoactive sexual arousal disorder; vaginal atrophy;dyspaneuria; atrophic vaginitis; benign prostatic hyperplasia (BPH) orhypertrophy or enlargement; bladder outlet obstruction; bladder painsyndrome (BPS); interstitial cystitis (IC); overactive bladder,neurogenic bladder and incontinence; diabetic nephropathy; (4) oculardiseases or disorders selected from glaucoma, retinopathy, diabeticretinopathy, blepharitis, dry eye syndrome, Sjögren's Syndrome; (5)hearing diseases or disorders selected from hearing impairment; partialor total hearing loss; partial or total deafness; tinnitus;noise-induced hearing loss; (6) topical or skin disorders or conditionsselected from dermal fibrosis, scleroderma, skin fibrosis; (7) woundhealing; wound healing in diabetics; microvascular perfusionimprovement; microvascular perfusion improvement following injury, tocounteract the inflammatory response in perioperative care; analfissures; diabetic ulcers; and (8) other diseases or conditions selectedfrom cancer metastasis; osteoporosis, gastroparesis; functionaldyspepsia; diabetic complications; diseases associated with endothelialdysfunction; and neurologic disorders associated with decreased nitricoxide production. 146-169. (canceled)
 170. The method of claim 145,wherein the compound is used in combination with one or more additionaltherapeutic agents.
 171. The method of claim 145, wherein the disease,health condition or disorder is myocardial infarction, stable orunstable angina pectoris; coronary spasms; variant angina; orPrinzmetal's angina.
 172. The method of claim 145, wherein the disease,health condition or disorder is selected from arterial hypertension,pulmonary hypertension, pulmonary arterial hypertension, resistanthypertension, diabetic hypertension, and portal hypertension.
 173. Themethod of claim 145, wherein the disease, health condition or disorderis selected from renal fibrosis, renal failure resulting from chronickidney diseases or insufficiency, chronic kidney disease, renal failuredue to accumulation/deposition and tissue injury, progressive sclerosis,glomerulonephritis, and polycystic kidney disease progression.
 174. Themethod of claim 145, wherein the disease, health condition or disorderis diabetic nephropathy.
 175. The method of claim 145, wherein thedisease, health condition or disorder is retinopathy or diabeticretinopathy.
 176. The method of claim 145, wherein the disease, healthcondition or disorder is selected from heart failure, congestive heartfailure, right heart hypertrophy, diastolic dysfunction, systolicdysfunction, heart failure/cardiorenal syndrome, coronary insufficiency,arrhythmias, reduction of ventricular preload and cardiac hypertrophy.177. The method of claim 145, wherein the disease, health condition ordisorder is heart failure, diastolic dysfunction, cardiorenal syndrome,or cardiac hypertrophy.
 178. The method of claim 145, wherein thedisease, health condition or disorder is renal fibrosis.
 179. The methodof claim 145, wherein the disease, health condition or disorder is renalfailure due to accumulation/deposition and tissue injury, progressivesclerosis, glomerulonephritis, and polycystic kidney diseaseprogression.
 180. The method of claim 145, wherein the disease, healthcondition or disorder is vaso-occlusive crisis.
 181. The method of claim145, wherein the disease, health condition or disorder is selected frompulmonary/respiratory conditions; pulmonary hypertension; pulmonaryarterial hypertension and associated pulmonary vascular remodeling;localized thrombosis and right heart hypertrophy; pulmonary hypertonia;primary pulmonary hypertension; secondary pulmonary hypertension;familial pulmonary hypertension; sporadic pulmonary hypertension,pre-capillary pulmonary hypertension; idiopathic pulmonary hypertension;thrombotic pulmonary arteriopathy; plexogenic pulmonary arteriopathy;cystic fibrosis; bronchoconstriction or pulmonary bronchoconstriction;acute respiratory distress syndrome; or lung fibrosis; and lungtransplant.
 182. The method of claim 145, wherein the disease, healthcondition or disorder is selected from pulmonary hypertension associatedwith or related to left ventricular dysfunction, hypoxemia, WHO groupsI, II, III, IV and V hypertensions, mitral valve disease, constrictivepericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis,pulmonary fibrosis, anomalous pulmonary venous drainage, pulmonaryvenooclusive disease, pulmonary vasculitis, collagen vascular disease,congenital heart disease, pulmonary venous hypertension, interstitiallung disease, sleep-disordered breathing, sleep apnea, alveolarhypoventilation disorders, chronic exposure to high altitude, neonatallung disease, alveolar-capillary dysplasia, sickle cell disease;coagulation disorders; chronic thromboembolism, pulmonary embolism dueto tumor, parasites or foreign material, connective tissue disease,lupus, schistosomiasis, sarcoidosis, chronic obstructive pulmonarydisease, asthma, emphysema, chronic bronchitis, pulmonary capillaryhemangiomatosis; histiocytosis X, and lymphangiomatosis and compressedpulmonary vessels due to adenopathy, tumor or fibrosing mediastinitis.183. The method of claim 145, wherein the disease, health condition ordisorder is cardiovascular disease associated with metabolic syndrome,obesity, dyslipidemia, diabetes, high blood pressure; lipid relateddisorders, dyslipidemia, hypercholesterolemia, hypertriglyceridemia,sitosterolemia, fatty liver disease, and hepatitis; preeclamsia; orsubcutaneous fat accumulation.
 184. The method of claim 145, wherein thedisease, health condition or disorder is selected from liver cirrhosis;liver cirrhosis associated with chronic liver disease; hepatic fibrosis,hepatic stellate cell activation, and hepatic fibrous collagen.
 185. Themethod of claim 145, wherein the disease, health condition or disorderis selected from cardiac interstitial fibrosis, cardiac remodeling andfibrosis.